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1
Chen, Xingchen, Darren Leahy, Jessica Van Haeften, Perry Hartfield, Peter J. Prentis, Chloé A. van der Burg, Joachim M. Surm, et al. "A Versatile and Robust Serine Protease Inhibitor Scaffold from Actinia tenebrosa." Marine Drugs 17, no. 12 (December 12, 2019): 701. http://dx.doi.org/10.3390/md17120701.
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Serine proteases play pivotal roles in normal physiology and a spectrum of patho-physiological processes. Accordingly, there is considerable interest in the discovery and design of potent serine protease inhibitors for therapeutic applications. This led to concerted efforts to discover versatile and robust molecular scaffolds for inhibitor design. This investigation is a bioprospecting study that aims to isolate and identify protease inhibitors from the cnidarian Actinia tenebrosa. The study isolated two Kunitz-type protease inhibitors with very similar sequences but quite divergent inhibitory potencies when assayed against bovine trypsin, chymostrypsin, and a selection of human sequence-related peptidases. Homology modeling and molecular dynamics simulations of these inhibitors in complex with their targets were carried out and, collectively, these methodologies enabled the definition of a versatile scaffold for inhibitor design. Thermal denaturation studies showed that the inhibitors were remarkably robust. To gain a fine-grained map of the residues responsible for this stability, we conducted in silico alanine scanning and quantified individual residue contributions to the inhibitor’s stability. Sequences of these inhibitors were then used to search for Kunitz homologs in an A. tenebrosa transcriptome library, resulting in the discovery of a further 14 related sequences. Consensus analysis of these variants identified a rich molecular diversity of Kunitz domains and expanded the palette of potential residue substitutions for rational inhibitor design using this domain.
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Luan, Hengjie, Mingkang Liu, Qinglin Shan, Yujing Jiang, Peng Yan, and Xiaoyu Du. "Experimental Study on the Effect of Mixed Thermodynamic Inhibitors with Different Concentrations on Natural Gas Hydrate Synthesis." Energies 17, no. 9 (April 26, 2024): 2078. http://dx.doi.org/10.3390/en17092078.
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Natural gas hydrate (NGH) is a potential future energy resource. More than 90% of NGH resources exist in the pore medium of seafloor sediments. During the development of deep-sea oil and gas fields, wellbore pipelines are often clogged due to the synthesis of gas hydrates, and the addition of thermodynamic inhibitors is a common solution to prevent hydrate synthesis. In this paper, the effects of two single inhibitors, sodium chloride and ethylene glycol, as well as hybrid inhibitors combining these two inhibitors on the synthesis of methane hydrates were investigated using the self-developed one-dimensional gas hydrate exploitation simulation test apparatus. The effects of single and hybrid inhibitors were investigated in terms of the hydrate synthesis volume and gas–water two-phase conversion rate. The results show that the hybrid inhibitor has a better inhibitory effect on hydrate synthesis with the same initial synthesis driving force. When the concentration of inhibitors is low, salt inhibitors can have a better inhibitory effect than alcohol inhibitors. However, in the mixed inhibitor experiment, increasing the proportion of ethylene glycol in the mixed inhibitor can more effectively inhibit the synthesis of hydrates than increasing the proportion of sodium chloride in the mixed inhibitor.
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Jasim, Haider Hadi, Read Abd Al-Hussain, and Ahmed Shawqi Sadeq. "Evaluation the Efficiency of Various Types of Corrosion Inhibitors Used for Basrah Water Storage Tanks." Al-Nahrain Journal for Engineering Sciences 23, no. 3 (November 21, 2020): 267–76. http://dx.doi.org/10.29194/njes.23030267.
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In this paper, the efficiency of six different types of corrosion inhibitors used in Basrah drinking water tanks was assessed using a potentiostatic test method. The mechanism of adsorption of silicate and phosphate inhibitors in AISI 316 stainless steel surfaces and the effects of different water components in inhibitors are discussed in detail. The values of corrosion rate obtained from the Potentiostatic test showed that the protection against corrosion in the presence of inhibitors is better compared to the case of absence of inhibitors. The results of the six types of corrosion inhibitors tested showed that the inhibitory efficacy is higher below the temperatures 45oC, but when raise the temperature above 45oC the inhibitory efficiency becomes to decrease. Also, the test results indicated that the corrosion inhibitor involves silicate products provided more inhibited efficiency compared to the phosphate inhibitor alone or used the combined silicate/phosphate corrosion inhibitor. The inspection of the surface of the tested samples using optical methods shows that the pitting corrosion is demonstrated on the specimen surfaces after testing with or without inhibitors.
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Arita, Minetaro, Takaji Wakita, and Hiroyuki Shimizu. "Cellular kinase inhibitors that suppress enterovirus replication have a conserved target in viral protein 3A similar to that of enviroxime." Journal of General Virology 90, no. 8 (August 1, 2009): 1869–79. http://dx.doi.org/10.1099/vir.0.012096-0.
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Previously, we identified a cellular kinase inhibitor, GW5074, that inhibits poliovirus (PV) and enterovirus 71 replication strongly, although its target has remained unknown. To identify the target of GW5074, we searched for cellular kinase inhibitors that have anti-enterovirus activity similar or related to that of GW5074. With this aim, we performed screenings to identify cellular kinase inhibitors that could inhibit PV replication cooperatively with GW5074 or synthetically in the absence of GW5074. We identified MEK1/2 inhibitors (SL327 and U0126), an EGFR inhibitor (AG1478) and a phosphatidylinositol 3-kinase inhibitor (wortmannin) as compounds with a cooperative inhibitory effect with GW5074, and an Akt1/2 inhibitor (Akt inhibitor VIII) as a compound with a synthetic inhibitory effect with MEK1/2 inhibitors and AG1478. Individual treatment with the identified kinase inhibitors did not affect PV replication significantly, but combined treatment with MEK1/2 inhibitor, AG1478 and Akt1/2 inhibitor suppressed the replication synthetically. The effect of AG1478 in this synthetic inhibition was compensated by other receptor tyrosine kinase inhibitors (IGF-1R inhibitor II and Flt3 inhibitor II). We isolated mutants resistant to Flt3 inhibitor II and GW5074 and found that these mutants had cross-resistance to each treatment. These mutants had a common mutation in viral protein 3A that results in an amino acid change at position 70 (Ala to Thr), a mutation that was previously identified in mutants resistant to a potent anti-enterovirus compound, enviroxime. These results suggest that cellular kinase inhibitors and enviroxime have a conserved target in viral protein 3A to suppress enterovirus replication.
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Cheng, Liwei, Limin Wang, Zhi Li, Bei Liu, and Guangjin Chen. "Inhibition Effect of Kinetic Hydrate Inhibitors on the Growth of Methane Hydrate in Gas–Liquid Phase Separation State." Energies 12, no. 23 (November 25, 2019): 4482. http://dx.doi.org/10.3390/en12234482.
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The effect of kinetic hydrate inhibitors (KHIs) on the growth of methane hydrate in the gas–liquid phase separation state is studied at the molecular level. The simulation results show that the kinetic inhibitors, named PVP and PVP-A, show good inhibitory effects on the growth of methane hydrate under the gas–liquid phase separation state, and the initial position of the kinetic hydrate inhibitors has a major effect on the growth of methane hydrates. In addition, inhibitors at different locations exhibit different inhibition performances. When the inhibitor molecules are located at the gas–liquid phase interface, increasing the contact area between the groups of the inhibitor molecules and methane is beneficial to enhance the inhibitory performance of the inhibitors. When inhibitor molecules are located at the solid–liquid phase interface, the inhibitor molecules adsorbed on the surface of the hydrate nucleus and decreased the direct contact of hydrate nucleus with the surrounding water and methane molecules, which would delay the growth of hydrate nucleus. Moreover, the increase of hydrate surface curvature and the Gibbs–Thomson effect caused by inhibitors can also reduce the growth rate of methane hydrate.
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Kunitada, Satoshi, and Takayasu Nagahara. "Factor Xa Inhibitors." Current Pharmaceutical Design 2, no. 5 (October 1996): 531–42. http://dx.doi.org/10.2174/1381612802666221004174926.
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Thrombin occupies a central position in thrombus formation and eventually has been a target to develop anticoagulant agents. Although both heparin and warfarin have been used as anticoagulants, a more useful, ideal anticoagulant is desired at bedside. Numerous efforts to develop a direct inhibitor of thrombin led to the discovery of improved anticoagulants including argatoroban. However, no orally available agent has been developed yet. FXa is responsible for prothrombin activation to generate thrombin and provides an alternative strategy to inhibit the coagulation cascade. In contrast with ATIII-dependent type FXa inhibitor, direct ATIII independent type inhibitors, such as tick anticoagulant peptide and antistasin, showed an inhibitory effect on arterial as well as venous thrombosis models, which was comparable to the effects of thrombin direct inhibitors or glycoprotein llb/Illa inhibitors. We synthesized a low molecular weight, orally active FXa inhibitor, DX- 9065l!, which also showed antithrombotic effect in various kind of thrombosis models. Further, FXa inhibitors have been known to have unique characteristics preferable to those of thrombin inhibitors. In this article, we review the pharmacological profile and structure-activity relationships of FXa inhibitors, ranging from naturally occuring to synthetic small molecular types.
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Milner, Malgorzata, Jadwiga Chroboczek, and Wlodzimierz Zagorski-Ostoja. "Engineered resistance against proteinases." Acta Biochimica Polonica 54, no. 3 (September 6, 2007): 523–36. http://dx.doi.org/10.18388/abp.2007_3226.
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Exogenous proteinase inhibitors are valuable and economically interesting protective biotechnological tools. We examined whether small proteinase inhibitors when fused to a selected target protein can protect the target from proteolytic degradation without simultaneously affecting the function and activity of the target domain. Two proteinase inhibitors were studied: a Kazal-type silk proteinase inhibitor (SPI2) from Galleria mellonella, and the Cucurbita maxima trypsin inhibitor I (CMTI I). Both inhibitors target serine proteinases, are small proteins with a compact structure stabilized by a network of disulfide bridges, and are expressed as free polypeptides in their natural surroundings. Four constructs were prepared: the gene for either of the inhibitors was ligated to the 5' end of the DNA encoding one or the other of two selected target proteins, the coat protein (CP) of Potato potyvirus Y or the Escherichia coli beta-glucuronidase (GUS). CMTI I fused to the target proteins strongly hampered their functions. Moreover, the inhibitory activity of CMTI I was retained only when it was fused to the CP. In contrast, when fused to SPI2, specific features and functions of both target proteins were retained and the inhibitory activity of SPI2 was fully preserved. Measuring proteolysis in the presence or absence of either inhibitor, we demonstrated that proteinase inhibitors can protect target proteins used either free or as a fusion domain. Interestingly, their inhibitory efficiency was superior to that of a commercial inhibitor of serine proteinases, AEBSF.
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Shi, Qizhen, Erin L. Kuether, Jocelyn A. Schroeder, Crystal L. Perry, Scot A. Fahs, and Robert R. Montgomery. "Factor VIII Inhibitors: Von Willebrand Factor Makes A Difference In Vitro and In Vivo." Blood 116, no. 21 (November 19, 2010): 709. http://dx.doi.org/10.1182/blood.v116.21.709.709.
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Abstract Abstract 709 The important association between von Willebrand factor (VWF) and factor VIII (FVIII) has been investigated for decades, but the effect of VWF on FVIII inhibitors is still controversial. Studies have demonstrated that some anti-FVIII inhibitory antibodies inhibit VWF-FVIII interaction, while others rely on the presence of VWF to inhibit FVIII activities. The influence of VWF on the Bethesda assay, which is routinely used in the clinic to determine the titer of FVIII-neutralizing inhibitors, is still uncertain because the plasma from hemophilia A patients with inhibitors contains normal levels of VWF. To explore the effect of VWF on the reactivity of FVIII inhibitors, we immunized VWF and FVIII double knockout (VWFnullFVIIInull) mice with recombinant human B-domain deleted FVIII (rhFVIII) to induce anti-FVIII inhibitory antibody development. Inhibitory plasma was collected and the titer of inhibitors was determined by Bethesda assay. Murine plasma-derived VWF (from FVIIInull mice) or recombinant human VWF (rhVWF) was used to study the influence of VWF on inhibitor inactivation of FVIII activity (FVIII:C). The remaining FVIII:C after inactivation was determined by chromogenic assay. When inhibitory plasma was incubated with rhFVIII in the presence of 1 U/ml VWF, the residual FVIII activity recovered was higher than in the absence of VWF, resulting in 6.82 ± 1.12 (n = 27) fold lower apparent inhibitor titers. This protective effect is VWF dose dependent. The source of VWF (plasma-derived murine VWF vs. rhVWF) did not affect its protection of FVIII from inhibitor inactivation and VWF does not affect FVIII:C measured in the chromogenic assay in the absence of inhibitors. Interestingly, we found that inhibitor inactivation of FVIII:C in the absence of VWF occurred much faster than in its presence. When the usual 2 hr. incubation at 37°C was omitted from the Bethesda assay, adding rhVWF to rFVIII before mixing with inhibitory plasma resulted in 67.29 ± 20.18 (n = 5) fold lower apparent inhibitor titers than without added VWF. In contrast, if VWF was added to inhibitory plasma first and then mixed with rhFVIII, the inhibitor titers were only 11.04 ± 3.56 (n = 5) fold lower than without added VWF. These results indicate that rhFVIII present in a preformed VWF-FVIII complex is protected from inhibitory antibody inactivation. Conversely, when VWF and inhibitory plasma are added to rhFVIII at the same time, the VWF and inhibitors appear to compete to bind to rhFVIII. Inhibitor titers were lower than in the absence of VWF, but the protective effect is not as efficient as when VWF and rhFVIII were already associated with one another before encountering inhibitors. To confirm the protective effect of VWF on FVIII from inhibitor inactivation, we infused FVIIInull or VWFnullFVIIInull mice with inhibitory plasma and rhFVIII followed by a tail clip survival test. When rhFVIII was infused into FVIIInull mice to 2% followed by inhibitory plasma infusion, all mice with inhibitor titer of 2.5 BU/ml (n = 4) survived tail clipping, and 2 of 4 survived with either 25 BU/ml or 250 BU/ml. If inhibitory plasma was infused first followed by rhFVIII infusion, then only 2 of 6 mice with inhibitor titers of 2.5 BU/ml survived tail clip challenge and none survived with 25 BU/ml and 250 BU/ml. In the first set of mice the infused FVIII was able to form a protective complex with endogenous VWF before encountering inhibitors, while in the second set FVIII is exposed to VWF and pre-infused inhibitory antibodies at the same time, a competitive binding that appears to reduce VWF's protective effect. In contrast, when rhFVIII was infused into VWFnullFVIIInull mice followed by inhibitory plasma infusion, no animals (n = 4 for each group) survived tail clipping with inhibitor titers of 2.5 BU/ml or higher. In summary, our studies demonstrate that VWF exerts a protective effect, reducing inhibitor inactivation of FVIII, both in vitro and in vivo. While the role of VWF in stabilizing plasma FVIII in a milieu rich in proteases has been appreciated for decades, our results indicate that treatment utilizing products containing a complex of FVIII with VWF may be especially beneficial in hemophilia A patients with inhibitors. Disclosures: No relevant conflicts of interest to declare.
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Savitri, Erna Noor, Putut Marwoto, and Sunyoto Eko Nugroho. "The Effectiveness of a Combination of Lime (Citrus aurantifolia.), Lerak (Sapindus rarak) and Jasmine Flower (Jasminum nudiflorum) Extracts as and Environmentally Friendly Corrosion Inhibitor." Jurnal Penelitian Pendidikan IPA 10, no. 3 (March 30, 2024): 1019–24. http://dx.doi.org/10.29303/jppipa.v10i3.6364.
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Corrosion can also be defined as the forced destruction of metal by the surrounding medium which is usually a liquid (corrosive agent). Corrosion prevention processes can be carried out, including by coating the metal surface, cathodic protection, adding corrosion inhibitors and so on. Several types of inhibitors that have been widely used in industrial applications are synthetic chemical inhibitors. However, the compounds of inhibitors are environmentally unfriendly, toxic and expensive. To overcome this problem, it is necessary to develop an environmentally friendly alternative corrosion inhibitor or better known as a green inhibitor. This research aims to test the effectiveness of using a combination of lime (Citrus aurantifolia.), Lerak (Sapindus rarak) and jasmine flower (Jasminum nudiflorum) extracts as an environmentally friendly corrosion inhibitor. The results obtained were inhibitors in the form of a combination which were added to the corrosive medium HCl which could reduce the rate of aluminum corrosion. This research also shows that time and concentration influence the corrosion rate. A higher concentration (200 ppm) has a greater inhibitory power than a concentration of 100 ppm. The best inhibitory power is found in 200 ppm inhibitor with a soaking time of 20 minutes
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Zeng, Peng, and Alvin Schmaier. "Ponatinib and other CML Tyrosine Kinase Inhibitors in Thrombosis." International Journal of Molecular Sciences 21, no. 18 (September 8, 2020): 6556. http://dx.doi.org/10.3390/ijms21186556.
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Abl1 kinase has important biological roles. The Bcr-Abl1 fusion protein creates undesired kinase activity and is pathogenic in 95% of chronic myeloid leukemia (CML) and 30% of acute lymphoblastic leukemia (ALL) patients. Targeted therapies to these diseases are tyrosine kinase inhibitors. The extent of a tyrosine kinase inhibitor’s targets determines the degree of biologic effects of the agent that may influence the well-being of the patient. This fact is especially true with tyrosine kinase inhibitor effects on the cardiovascular system. Thirty-one percent of ponatinib-treated patients, the tyrosine kinase inhibitor with the broadest inhibitory spectrum, have thrombosis associated with its use. Recent experimental investigations have indicated the mechanisms of ponatinib-associated thrombosis. Further, an antidote to ponatinib is in development by re-purposing an FDA-approved medication.
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Mandawara, Vineeta, and Dr Alok Chaturvedi. "Corrosion Inhibition of Copper Metal by Ethanolic Extract of Tinospora Cordifolia Plant in Sulfuric and Hydrochloric Acids of varying Strength (0.5 N to 3N) using Additives." International Journal for Research in Applied Science and Engineering Technology 11, no. 6 (June 30, 2023): 352–72. http://dx.doi.org/10.22214/ijraset.2023.53444.
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Abstract: Using typical weight loss and thermometric techniques, the inhibitory impact of Tinospora cordifolia stem and leaf extract on copper corrosion in H2SO4 and HCl solutions of varying strength( 0.5N,1N,2N,3N) was investigated. The outcomes demonstrated that extracts worked as outstanding and effective inhibitors in acidic conditions, both in the absence and addition of additives. In an acidic environment, Tinospora cordifolia stem extract outperformed leaves extract in terms of inhibitory efficiency.The maximal inhibitory efficiency for stem extract at maximum inhibitor concentrations of 0.8% was 96.54% and 99.19% in 0.5 N H2SO4 and 95.26% & 97.78% in 0.5 N HCl, respectively, in the absence and presence of additives (KI & K2SO4). Similar to this, the effectiveness of the leaf extract's inhibition was 95.37% and 97.84% in 0.5 N H2SO4 and 94.15% and 96.92% in 0.5 N HCl, at a maximum inhibitor concentration of 0.8% in the absence and addition, respectively, of additives (KI & K2SO4). Based on the findings, stem extract suppresses H2SO4 and HCl more potently than leaf extract.Surface coverage (θ) grows as inhibitor concentration rises (from 0.2% to 0.8%).The values of log(θ/(1-θ) increase linearly as inhibitor concentration rises,it has been demonstrated that ,the inhibitor's adsorption on the copper surface in the acid solutions followed Langmuir's adsorption isotherm. The current investigation discovered that the inhibitors (stem and leaf) were more effective at inhibiting the metal copper in H2SO4 and HCl acid solutions when an additive (KI and K2SO4) was present than when the inhibitors (stem and leaf) were present alone. Synergistic effects are to blame for this. The combined action of the two chemicals is more potent on a metal surface than the combined actions of the two chemicals acting separately or concurrently.
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Sever, Natasa, Metka Filipic, Joze Brzin, and Tamara T. Lah. "Effect of Cysteine Proteinase Inhibitors on Murine B16 Melanoma Cell Invasion in vitro." Biological Chemistry 383, no. 5 (May 15, 2002): 839–42. http://dx.doi.org/10.1515/bc.2002.088.
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Abstract Various types of proteinases are implicated in the malignant progression of human and animal tumors. Proteinase inhibitors may therefore be useful as therapeutic agents in antiinvasive and antimetastatic treatment. The aims of this study were (1) to estimate the relative importance of proteinases in B16 cell invasion in vitro using synthetic, classspecific proteinase inhibitors and (2) to assess the inhibitory effect of some naturally occurring cysteine proteinase inhibitors. Serine proteinase inhibitor reduced invasiveness by up to 24%, whereas inhibition of aspartic proteinases reduced invasion by 11%. Synthetic inhibitors of cysteine proteinases markedly impaired invasion: cathepsin B inhibitors, particularly Ca 074Me, inhibited invasion from 20 40%, whereas cathepsin L inhibitor Clik 148 reduced invasion by 11%. The potato cysteine proteinase inhibitor PCPI 8.7 inhibited invasion by 21%, whereas another potato inhibitor, PCPI 6.6, and the mushroom cysteine proteinase inhibitor clitocypin had no effects. As the inhibitors that inhibited cathepsin B were in general more efficient at impairing the invasiveness, we conclude that of the two cysteine proteinases, cathepsin B plays a more important role than cathepsin L in murine melanoma cell invasion.
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ZHAN, JIN-HUI, XI ZHAO, XU-RI HUANG, and CHIA-CHUNG SUN. "MOLECULAR DYNAMICS AND FREE ENERGY ANALYSES OF ERK2–PYRAZOLYLPYRROLE INHIBITORS INTERACTIONS: INSIGHT INTO STRUCTURE-BASED LIGAND DESIGN." Journal of Theoretical and Computational Chemistry 08, no. 05 (October 2009): 887–908. http://dx.doi.org/10.1142/s0219633609005131.
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The extracellular signal-regulated protein kinase 2 (ERK2) is a pivotal member involving in Ras/Raf/MEK/ERK signal transduction pathway, acting as a central point where multiple signaling pathways coalesce to drive transcription. The pyrazolylpyrrole compounds as ATP competitive inhibitors of ERK2 can bind target with a special binding mode and have higher inhibitory potency than other ERK2-inhibitors. We investigated the interaction mode of ERK2-inhibitor using molecular dynamics simulation. The molecular mechanics Poisson–Boltzmann surface area approach is used to calculate the binding free energy of ERK2 with pyrazolylpyrrole inhibitors to analyze the factors of improving the affinity. The results indicated that the electrostatic interactions play the most important role in keeping the stabilization of ERK2-inhibitor. The structural analyses showed that the protein motions can be controlled by changing the structures of inhibitors; furthermore, the full use of available space in the binding site by improving the flexibilities of inhibitors and introducing hydrophobic groups can increase the inhibitory effect.
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Sharma, Rajesh, Jitendra Sainy, and Subhash Chaturvedi. "2-Amino-5-sulfanyl-1,3,4-thiadiazoles: A new series of selective cyclooxygenase-2 inhibitors." Acta Pharmaceutica 58, no. 3 (September 1, 2008): 317–26. http://dx.doi.org/10.2478/v10007-008-0011-6.
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2-Amino-5-sulfanyl-1,3,4-thiadiazoles: A new series of selective cyclooxygenase-2 inhibitorsA new series of cyclooxygenase-2 inhibitors with 2-amino--5-sulfanyl-1,3,4-thiadiazole as the central scaffold unit has been synthesized. The newly synthesized compounds were characterized by analytical and spectral methods. Compounds were screened for cyclooxygenase inhibitory activity by the colorimetric COX (ovine) inhibitor screening assay, anti-inflammatory activity by the carrageenean induced rat paw oedema test and analgesic activity by the tail flick method. Some compounds exhibited significant biological activity.
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Na, Bon Hyang, Thi Xoan Hoang, and Jae Young Kim. "Hsp90 Inhibition Reduces TLR5 Surface Expression and NF-κB Activation in Human Myeloid Leukemia THP-1 Cells." BioMed Research International 2018 (2018): 1–8. http://dx.doi.org/10.1155/2018/4319369.
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Tumors highly express active heat shock protein 90 (Hsp90), which is involved in tumor survival and progression. Enhanced Toll-like receptor (TLR) 5 expression and signaling were reported to be associated with acute myeloid leukemia. In the present study, we investigated the possible modulatory effects of Hsp90 inhibitors on TLR5 expression and signaling in the human myeloid leukemia cell line THP-1. Cells were pretreated with various concentrations of the Hsp90 inhibitor geldanamycin (GA) or the Hsp70 inhibitor VER155008, followed by stimulation with bacterial flagellin. Flagellin-induced nuclear factor-κB (NF-κB) activation was significantly reduced by treatment with GA or VER155008. To elucidate the underlying mechanism of this effect, mRNA and cell surface expression of TLR5 was examined. TLR5 mRNA expression was enhanced by both GA and VER155008, whereas cell surface expression of TLR5 was reduced by three different Hsp90 inhibitors, including GA, 17-(allylamino)-17-demethoxygeldanamycin, and radicicol, and an Hsp70 inhibitor. The inhibitory effect of Hsp90 inhibitors was much higher than that of Hsp70 inhibitor. Our results suggest that Hsp90 inhibitors suppress TLR5 surface expression and activation of NF-κB in THP-1 cells in response to TLR5 ligand, and these inhibitory effects may be associated with the possible mechanisms by which Hsp90 inhibitors suppress myeloid leukemia.
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Yan, Daojing, Jiakun Xu, Xiang Wang, Jiaxing Zhang, Gang Zhao, Yingwu Lin, and Xiangshi Tan. "Spiro-Oxindole Skeleton Compounds Are Efficient Inhibitors for Indoleamine 2,3-Dioxygenase 1: An Attractive Target for Tumor Immunotherapy." International Journal of Molecular Sciences 23, no. 9 (April 23, 2022): 4668. http://dx.doi.org/10.3390/ijms23094668.
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Indoleamine 2,3-dioxygenase 1 (IDO1) is an attractive heme enzyme for its significant function in cancer immunotherapy. Potent IDO1 inhibitors have been discovered for decades, whereas no clinical drugs are used for cancer treatment up to now. With the goal of developing medically valuable IDO inhibitors, we performed a systematic study of SAR405838 analogs with a spiro-oxindole skeleton in this study. Based on the expression and purification of human IDO1, the inhibitory activity of spiro-oxindole skeleton compounds to IDO1 was evaluated by IC50 and Ki values. The results demonstrated that inhibitor 3 exhibited the highest IDO1 inhibitory activity with IC50 at 7.9 μM among all inhibitors, which is ~six-fold of the positive control (4−PI). Moreover, inhibitor 3 was found to have the most effective inhibition of IDO1 in MCF-7 cancer cells without toxic effects. Molecular docking analysis revealed that the hydrophobic interaction stabilized the binding of inhibitor 3 to the IDO1 active site and made an explanation for the uncompetitive mode of inhibitors. Therefore, this study provides valuable insights into the screen of more potent IDO1 inhibitors for cancer immunotherapy.
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Han, Di, Huiqun Wang, Wei Cui, Beibei Zhang, and Bo-Zhen Chen. "Computational insight into the mechanisms of action and selectivity of Afraxis PAK inhibitors." Future Medicinal Chemistry 12, no. 5 (March 2020): 367–85. http://dx.doi.org/10.4155/fmc-2019-0273.
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Aim: The p21-activated kinases (PAKs) are involved in many important biological activity regulations. FRAX019, FRAX414, FRAX597, FRAX1036 and G-5555 were identified as PAKs inhibitors. Their detailed inhibitory mechanisms deserve further investigation. Results: Molecular dynamics simulations and further calculations for the PAK1/inhibitor and PAK4/inhibitor complexes indicate that their binding free energies are basically consistent with the trend of experimental activity data. Conclusion: The anchoring of residues Leu347PAK1 and Leu398PAK4 is the structural basis for designing Afraxis PAK inhibitors. This study discloses the inhibitory mechanisms of FRAX019, FRAX414, FRAX597, FRAX1036 and G-5555 toward PAK1 and PAK4 and some clues to enhance kinase activities and selectivities, which will provide valuable information to the development of more potent and selective PAK inhibitors.
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Umezawa, Koji, and Isao Kii. "Druggable Transient Pockets in Protein Kinases." Molecules 26, no. 3 (January 27, 2021): 651. http://dx.doi.org/10.3390/molecules26030651.
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Drug discovery using small molecule inhibitors is reaching a stalemate due to low selectivity, adverse off-target effects and inevitable failures in clinical trials. Conventional chemical screening methods may miss potent small molecules because of their use of simple but outdated kits composed of recombinant enzyme proteins. Non-canonical inhibitors targeting a hidden pocket in a protein have received considerable research attention. Kii and colleagues identified an inhibitor targeting a transient pocket in the kinase DYRK1A during its folding process and termed it FINDY. FINDY exhibits a unique inhibitory profile; that is, FINDY does not inhibit the fully folded form of DYRK1A, indicating that the FINDY-binding pocket is hidden in the folded form. This intriguing pocket opens during the folding process and then closes upon completion of folding. In this review, we discuss previously established kinase inhibitors and their inhibitory mechanisms in comparison with FINDY. We also compare the inhibitory mechanisms with the growing concept of “cryptic inhibitor-binding sites.” These sites are buried on the inhibitor-unbound surface but become apparent when the inhibitor is bound. In addition, an alternative method based on cell-free protein synthesis of protein kinases may allow the discovery of small molecules that occupy these mysterious binding sites. Transitional folding intermediates would become alternative targets in drug discovery, enabling the efficient development of potent kinase inhibitors.
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Tremblay, Cécile L., Françoise Giguel, Christopher Kollmann, Yongbiao Guan, Ting-Chao Chou, Bahige M. Baroudy, and Martin S. Hirsch. "Anti-Human Immunodeficiency Virus Interactions of SCH-C (SCH 351125), a CCR5 Antagonist, with Other Antiretroviral Agents In Vitro." Antimicrobial Agents and Chemotherapy 46, no. 5 (May 2002): 1336–39. http://dx.doi.org/10.1128/aac.46.5.1336-1339.2002.
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ABSTRACT SCH-C (SCH 351125) is a small-molecule antagonist of the human immunodeficiency virus type 1(HIV-1) coreceptor CCR5. It has in vitro activity against R5 viruses with 50% inhibitory concentrations ranging from 1.0 to 30.9 nM. We have studied anti-HIV-1 interactions of SCH-C with other antiretroviral agents in vitro. Synergistic interactions were seen with nucleoside reverse transcriptase inhibitors (zidovudine and lamivudine), nonnucleoside reverse transcriptase inhibitors (efavirenz), and protease inhibitors (indinavir) at all inhibitory concentrations evaluated. We have also studied antiviral interactions between the HIV-1 fusion inhibitor T-20 and SCH-C against a panel of R5 HIV-1 isolates. We found synergistic interactions against all the viruses tested, some of which harbored resistance mutations to reverse transcriptase and protease inhibitors. Anti-HIV-1 synergy was also observed between SCH-C and another R5 virus inhibitor, aminooxypentane-RANTES. These findings suggest that SCH-C may be a useful anti-HIV drug in combination regimens and that a combination of chemokine coreceptor/fusion inhibitors may be useful in the treatment of multidrug-resistant viruses.
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Schmidt, Anja, Kerstin Brettschneider, Jörg Kahle, Aleksander Orlowski, Karin Becker-Peters, Diana Stichel, Jörg Schulze, et al. "Neutralisation of factor VIII inhibitors by anti-idiotypes isolated from phage-displayed libraries." Thrombosis and Haemostasis 116, no. 07 (January 2016): 32–41. http://dx.doi.org/10.1160/th15-12-0925.
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SummaryFollowing replacement therapy with coagulation factor VIII (FVIII), up to 30 % of haemophilia A patients develop FVIII-specific inhibitory antibodies (FVIII inhibitors). Immune tolerance induction (ITI) is not always successful, resulting in a need for alternative treatments for FVIII inhibitor-positive patients. As tolerance induction in the course of ITI appears to involve the formation of anti-idiotypes specific for anti-FVIII antibodies, such anti-idiotypes might be used to restore haemostasis in haemophilia A patients with FVIII inhibitors. We isolated antiidiotypic antibody fragments (scFvs) binding to murine FVIII inhibitors 2-76 and 2-77 from phage-displayed libraries. FVIII inhibitor/anti-idiotype interactions were very specific as no cross-reactivity with other FVIII inhibitors or isotype controls was observed. ScFvs blocked binding of FVIII inhibitors to FVIII and neutralised their cognate inhibitors in vitro and a monoclonal mouse model. In addition, scFv JkH5 specific for FVIII inhibitor 2-76 stained 2-76-producing hybridoma cells. JkH5 residues R52 and Y226, located in complementary determining regions, were identified as crucial for the JkH5/2-76 interaction using JkH5 alanine mutants. SPR spectroscopy revealed that JkH5 interacts with FVIII inhibitor 2-76 with nanomolar affinity. Thus, FVIII inhibitorspecific, high-affinity anti-idiotypes can be isolated from phagedisplayed libraries and neutralise their respective inhibitors. Furthermore, we show that anti-idiotypic scFvs might be utilised to specifically target inhibitor-specific B cells. Hence, a pool of anti-idiotypes could enable the reestablishment of haemostasis in the presence of FVIII inhibitors in patients or even allow the depletion of inhibitors by targeting inhibitor-specific B cell populations.
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Böhm, Martina, Manuela Krause, Charis Von Auer, Wolfgang Miesbach, and Inge Scharrer. "The Frequency and the Significance of ADAMTS-13 Neutralising Inhibitors in 62 Patients with Non-Familial Thrombotic Thrombocytopenic Purpura." Blood 104, no. 11 (November 16, 2004): 3945. http://dx.doi.org/10.1182/blood.v104.11.3945.3945.
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Abstract Neutralising inhibitors against ADAMTS-13 are detected in 51–67% of patients with Thrombotic Thrombocytopenic Purpura (TTP). These ADAMTS-13 inhibitors have not been very well characterised and the diagnostic or the prognostic value of these inhibitors is not established. In the present study, we measured ADAMTS-13 activity and the corresponding inhibitor titer in 96 samples from 62 patients with TTP at various stages of their disease. All patients presented with non-familial TTP. For patients with severe ADAMTS-13 activity without detectable inhibitor heritable ADAMTS-13 deficiency was excluded by either normalisation of ADAMTS-13 activity in remission or by detecting normal ADAMTS-13 activity in first degree family members. ADAMTS-13 activity was quantified by measuring the residual ristocetin cofactor activity of the substrate. The inhibitor against ADAMTS-13 was detected by mixing patient plasma, either neat or diluted, with normal plasma. The inhibitor concentration neutralising 50% of ADAMTS-13 activity in a 1:1 dilution of patient plasma with normal plasma was defined as 1 U/ml. Inhibitors were considered non-detectable (<0.4 U/ml), if residual ADAMTS-13 activity in the mixture was higher than 75%. Samples with ADAMTS-13 activity >6.25% were heat-inactivated (30 min at 56°C) before testing for inhibitory activity. We found severe ADAMTS-13 deficiency in 89% (24/27) of the samples from patients with acute untreated TTP. 87% (21/24) of these samples were positive for inhibitory activity. The inhibitor titer ranged from 0.4 to 62 U/ml with a median of 1 U/ml. One patient with acute TTP demonstrated ADAMTS-13 activity of 34% despite an inhibitor titer of 0.6 U/ml. The sensitivity of a positive inhibitor test for the diagnosis of TTP was thus 82%. The inhibitor titer before initiation of therapy could not be correlated with the platelet count, the CRP-level or the response to PE-therapy, if patients with an index episode and patients with a relapse were analysed separately. Severe ADAMTS-13 activity was detected in 15/31 samples collected from patients during plasma exchange therapy. 93% (14/15) of these samples were positive for an inhibitor with a titer ranging between 0.6 and 47 U/ml (median: 3 U/ml). 12 of 37 patients tested in remission presented with severe ADAMTS-13 deficiency, 6 of them were positive for inhibitory activity (range: 1–52 U/ml; median: 5 U/ml). The inhibitor titer for patients, which were analysed during acute untreated TTP as well as in remission (n=5), was notable not related to the stage of disease. Five patients with positive inhibitory activity at admission demonstrated mild ADAMTS-13 deficiency in remission without detectable inhibitor. In contrast, we detected inhibitory activity of 0,6–0,8 U/ml in 3 samples from two patients with measurable ADAMTS-13 activity. These low titer inhibitors were only detectable, if samples were heat inactivated before performing the inhibitor assay. Our data demonstrate, that inhibitors against ADAMTS-13 are very heterogeneous. It is highly suspected, that some of these inhibitors can either completely or partly neutralise ADAMTS-13 function in vivo without being detectable in vitro. Inhibitors against ADAMTS-13 might, on the other side, not always completely inhibit ADAMTS-13 function, since they can occur in patients with high residual ADAMTS-13 activity. Inhibitor titers show a wide variation and the clinical significance of the inhibitor titer before, during and after therapy needs to be further investigated.
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Domoney, C., and T. Welham. "Trypsin inhibitors in Pisum: variation in amount and pattern of accumulation in developing seed." Seed Science Research 2, no. 3 (September 1992): 147–54. http://dx.doi.org/10.1017/s0960258500001276.
Full textAbstract:
AbstractA survey of Pisum genotypes for seed trypsin inhibitors revealed a tenfold range in the extent of inhibition. Approximately 90% of trypsin inhibitory activity was associated with two albumin fractions in selected variant lines. The differences among extreme variants were consistent in three environments, between two sources of trypsin tested and whether expressed on a unit protein or dry weight basis.A study of the appearance of trypsin inhibitors during seed development in selected highand low-inhibitor lines showed differences in the accumulation pattern of active inhibitors. An endogenous protease was identified in Pisum seed protein preparations, whose in vitro trypsin-like activity was predominant in protein from early stages of seed development, when little or no trypsin inhibitor was present. However, there was no correlation between the amount of this protease and the extent of trypsin inhibitory activity in lines that varied for inhibitor content.
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Scandella, D., M. Mattingly, S. de Graaf, and CA Fulcher. "Localization of epitopes for human factor VIII inhibitor antibodies by immunoblotting and antibody neutralization." Blood 74, no. 5 (October 1, 1989): 1618–26. http://dx.doi.org/10.1182/blood.v74.5.1618.1618.
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Abstract Human factor VIII(FVIII) inhibitors are pathologic, circulating antibodies that inactivate FVIII. We have examined the location of epitopes on the FVIII protein for inhibitors from hemophilia A and nonhemophilic individuals. The inhibitors were of type I or type II in the kinetics of their inactivation of FVIII. A cDNA clone of human FVIII was used to express defined FVIII protein fragments in Escherichia coli for immunoblotting with inhibitor plasma. An epitope for 18 heavy-chain inhibitors was localized to the aminoterminal 18.3 Kd of the A2 domain. Two of these inhibitors also recognized an epitope located between A1 and A2 domains. Similarly, an epitope for 23 light- chain inhibitors was localized to the C2 domain. Weaker epitopes for 13 of the same inhibitors within the C1 and C2 domains were also observed. Four of the 23 inhibitors in addition bound strongly to the A3 domain. Most inhibitors (22 of 23) were neutralized in vitro only by the FVIII fragments to which they bound on immunoblots; however, one inhibitor that was neutralized by a fragment containing the A1 domain did not bind to it on immunoblots. Conversely, 3 of 3 inhibitors that bound to the A3 domain and 5 of 15 that bound to the A2 domain were not neutralized by the corresponding fragments. The epitope specificity of an inhibitor did not depend on its source or type. Our results show that FVIII inhibitors bind to limited areas within the heavy and light chains of FVIII. Some inhibitor plasmas contain additional antibodies that may not be inhibitory.
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Scandella, D., M. Mattingly, S. de Graaf, and CA Fulcher. "Localization of epitopes for human factor VIII inhibitor antibodies by immunoblotting and antibody neutralization." Blood 74, no. 5 (October 1, 1989): 1618–26. http://dx.doi.org/10.1182/blood.v74.5.1618.bloodjournal7451618.
Full textAbstract:
Human factor VIII(FVIII) inhibitors are pathologic, circulating antibodies that inactivate FVIII. We have examined the location of epitopes on the FVIII protein for inhibitors from hemophilia A and nonhemophilic individuals. The inhibitors were of type I or type II in the kinetics of their inactivation of FVIII. A cDNA clone of human FVIII was used to express defined FVIII protein fragments in Escherichia coli for immunoblotting with inhibitor plasma. An epitope for 18 heavy-chain inhibitors was localized to the aminoterminal 18.3 Kd of the A2 domain. Two of these inhibitors also recognized an epitope located between A1 and A2 domains. Similarly, an epitope for 23 light- chain inhibitors was localized to the C2 domain. Weaker epitopes for 13 of the same inhibitors within the C1 and C2 domains were also observed. Four of the 23 inhibitors in addition bound strongly to the A3 domain. Most inhibitors (22 of 23) were neutralized in vitro only by the FVIII fragments to which they bound on immunoblots; however, one inhibitor that was neutralized by a fragment containing the A1 domain did not bind to it on immunoblots. Conversely, 3 of 3 inhibitors that bound to the A3 domain and 5 of 15 that bound to the A2 domain were not neutralized by the corresponding fragments. The epitope specificity of an inhibitor did not depend on its source or type. Our results show that FVIII inhibitors bind to limited areas within the heavy and light chains of FVIII. Some inhibitor plasmas contain additional antibodies that may not be inhibitory.
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Liang, Jianhuai, Bingfeng Wang, Yang Yang, Boping Liu, and Yulong Jin. "Approaching the Dimerization Mechanism of Small Molecule Inhibitors Targeting PD-L1 with Molecular Simulation." International Journal of Molecular Sciences 24, no. 2 (January 9, 2023): 1280. http://dx.doi.org/10.3390/ijms24021280.
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Inhibitors blocking the PD-1/PD-L1 immune checkpoint demonstrate impressive anti-tumor immunity, and small molecule inhibitors disclosed by the Bristol-Myers Squibb (BMS) company have become a hot topic. In this work, by modifying the carbonyl group of BMS-202 into a hydroxyl group to achieve two enantiomers (MS and MR) with a chiral center, we found that this is an effective way to regulate its hydrophobicity and thus to reduce the negative effect of polar solvation free energy, which enhances the stability of PD-L1 dimer/inhibitor complexes. Moreover, we studied the binding modes of BMS-200 and BMS-202-related small molecule inhibitors by molecular dynamics simulation to explore their inhibitory mechanism targeting PD-L1 dimerization. The results showed that the size exclusion effect of the inhibitors triggered the rearrangement of the residue ATyr56, leading to the formation of an axisymmetric tunnel-shaped pocket, which is an important structural basis for improving the binding affinity of symmetric inhibitors with PD-L1. Furthermore, after inhibitor dissociation, the conformation of ATyr123 and BMet115 rearranged, which blocked the entrance of the binding pocket, while the reverse rearrangements of the same residues occurred when the PD-L1 monomer was complexed with the inhibitors, preparing PD-L1 for dimerization. Overall, this study casts a new light on the inhibitory mechanism of BMS inhibitors targeting PD-L1 dimerization and provides an idea for designing novel small molecule inhibitors for future cancer immunotherapy.
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Potempa, J., J. J. Enghild, and J. Travis. "The primary elastase inhibitor (elastasin) and trypsin inhibitor (contrapsin) in the goat are serpins related to human α1-anti-chymotrypsin." Biochemical Journal 306, no. 1 (February 15, 1995): 191–97. http://dx.doi.org/10.1042/bj3060191.
Full textAbstract:
Two primary serine proteinase inhibitors in goat plasma have been isolated and characterized. The N-terminal sequence analysis of the purified proteins revealed that they are closely related to each other and are highly homologous to human alpha 1-anti-chymotrypsin rather than alpha 1-proteinase inhibitor. However, despite structural similarities the inhibitory specificity of the goat inhibitors differed from each other and from that of anti-chymotrypsin. In contrast with human anti-chymotrypsin, one of the goat inhibitors was shown to be a strong and specific inhibitor of trypsin (k(ass.) = 1.9 x 10(6) M-1.s-1), whereas the other was an efficient inhibitor of neutrophil elastase (k(ass.) = 1.5 x 10(6) M-1.S-1). Differences in the inhibitory specificity of each protein could readily be attributed to the amino acid sequence within the reactive site region. The trypsin inhibitor with an assumed arginine residue at the P1 position of the reactive-site peptide bond is referred to as ‘contrapsin’, and indicates that the occurrence of contrapsins is not restricted to rodents. In contrast, the inhibitory specificity, resistance to oxidative and proteolytic inactivation and the presence of a P1 leucine residue in the elastase inhibitor is unique among inhibitory serpins that have been characterized to date. Because this serpin is apparently the major elastase inhibitor in goat plasma, it is likely to be involved in the control of goat neutrophil elastase. Therefore, we suggest the name ‘elastasin’, and extend it to any other anti-chymotrypsin related serpins possessing neutrophil-elastase- inhibitory activity.
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Sato, Shun, Kana Yamamoto, Moeno Ito, Katsutoshi Nishino, Takanao Otsuka, Kazuhiro Irie, and Masaya Nagao. "Enhancement of Inhibitory Activity by Combining Allosteric Inhibitors Putatively Binding to Different Allosteric Sites on Cathepsin K." Molecules 28, no. 10 (May 19, 2023): 4197. http://dx.doi.org/10.3390/molecules28104197.
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Background: Cathepsin K, which is involved in bone resorption, is a good target for treating osteoporosis, but no clinically approved medicine has been developed. Recently, allosteric inhibitors with high specificity and few side effects have been attracting attention for use in new medicines. Methods: Cathepsin K inhibitors were isolated from the methanol extract of Chamaecrista nomame (Leguminosae) using cathepsin K inhibition activity-assisted multi-step chromatography. Standard kinetic analysis was employed to examine the mechanism of cathepsin K inhibition when an isolated inhibitor and its derivative were used. The allosteric binding of these cathepsin K inhibitors was supported by a docking study using AutoDock vina. Combinations of allosteric cathepsin K inhibitors expected to bind to different allosteric sites were examined by means of cathepsin K inhibition assay. Results: Two types of cathepsin K inhibitors were identified in the methanol extract of Chamaecrista nomame. One type consisted of cassiaoccidentalin B and torachrysone 8-β-gentiobioside, and inhibited both cathepsin K and B with similar inhibitory potential, while the other type of inhibitor consisted of pheophytin a, and inhibited cathepsin K but not cathepsin B, suggesting that pheophytin a binds to an allosteric site of cathepsin K. Kinetic analysis of inhibitory activity suggested that pheophytin a and its derivative, pheophorbide b, bind allosterically to cathepsin K. This possibility was supported by a docking study on cathepsin K. The cathepsin K inhibitory activity of pheophytin a and pheophorbide b was enhanced by combining them with the allosteric inhibitors NSC 13345 and NSC94914, which bind to other allosteric sites on cathepsin K. Conclusions: Different allosteric inhibitors that bind to different sites in combination, as shown in this study, may be useful for designing new allosteric inhibitory drugs with high specificity and few side effects.
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Flores-Garcia, N. S., C. D. Arrieta-Gonzalez, J. J. Ramos-Hernandez, G. K. Pedraza-Basulto, J. G. Gonzalez-Rodriguez, J. Porcayo-Calderon, and L. Martinez-Gomez. "Rare Earth-Based Compounds as Inhibitors of Hot-Corrosion Induced by Vanadium Salts." Materials 12, no. 22 (November 19, 2019): 3796. http://dx.doi.org/10.3390/ma12223796.
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In this study, the performance evaluation of lanthanum compounds as corrosion inhibitors of vanadium salts was performed. The inhibitors tested were lanthanum acetate and La2O3. The performance of the inhibitors was tested using sodium metavanadate (NaVO3) as a corrosive medium at 700, 800, and 900 °C. The corrosion inhibitory effect was evaluated on the corrosion process of 304H stainless steel. The corrosion rate of the steel was determined by the mass loss technique after 100 h of immersion in the corrosive salt with and without the addition of the corrosion inhibitor. The results show that lanthanum compounds act as corrosion inhibitors of vanadium salts. The inhibitory effect increases by increasing the concentration and tends to decrease when increasing the test temperature. Lanthanum compounds act as excellent corrosion inhibitors due to their ability to stabilize vanadium cations. Vanadium is stabilized by forming a new compound, lanthanum vanadate (LaVO4), with a melting point much higher than the compounds formed when Mg or Ni compounds are used as corrosion inhibitors.
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Panneerselvi, V., P. Muthukrishnan, K. Shankar, and K. Prabakaran. "A Facile One Pot Synthesis and Anticorrosion Potential of Carbazole Linked Quinoline Moiety." Asian Journal of Chemistry 36, no. 1 (December 31, 2023): 229–38. http://dx.doi.org/10.14233/ajchem.2024.30888.
Full textAbstract:
A facile and efficient one pot synthesis has been developed for the preparation of quinoline-substituted carbazoles 3-(4-carboxyquinolin-2-yl)-9-methyl-9H-carbazole (Cbz-QCA) and 3-(4-chloroquinolin-2-yl)-9-methyl-9H-carbazole (Cbz-ClQ) by treating 3-acetyl-9-methyl-9H-carbazole (3Ac-Cbz), with isatin under Pfitzinger reaction conditions and utilizing anthranilic acid in the presence of POCl3 through the modified Niementowski method, respectively. The synthesized compounds have been comprehensively characterized through spectral data. The effect of 3Ac-Cbz (1), Cbz-QCA (2) and Cbz-ClQ (3) were assessed as a steel corrosion inhibitor in molar hydrochloric acid using weight loss, potentiodynamic polarization, and electrochemical methods. The inhibitory effect rises with tested inhibitor concentration, reaching above 84% at higher concentrations of all tested inhibitors. These results indicated that tested inhibitors have a good corrosion inhibition. An increase in the inhibitor’s concentration leads to a higher percentage of inhibition efficiency, driven by the adsorption of inhibitor molecules onto the metal surface. Results from scanner electron microscopy (SEM) support the experimental inhibition tests have yielded successful outcomes and validate the adsorption process.
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Jang, Seong, Bill Strickland, Lynda Finis, Jeffrey J. Koojiman, Janneke J. Melis, Guido J. Zaman, and Jan V. Tornout. "Abstract 4014: Comparative biochemical kinase activity analysis identifies rivoceranib as the most selective VEGFR-2 inhibitor compared with other TKIs with known activity against VEGFR-2." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4014. http://dx.doi.org/10.1158/1538-7445.am2023-4014.
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Abstract Introduction: Vascular endothelial growth factor receptor 2 (VEGFR-2) is a key regulator of tumor angiogenesis that is highly expressed in several tumor types and is a known target for anti-cancer therapy. Yet the clinical use of VEGFR-2 inhibitors has been challenged by limited efficacy and various side effects, potentially due to the low selectivity of these TKIs for VEGFR-2. Thus, potent VEGFR-2 inhibitors with improved selectivity are needed. Rivoceranib is an oral tyrosine kinase inhibitor (TKI) that potently and selectively inhibits VEGFR-2. A comparison of the potency and selectivity of VEGFR-2 inhibitors can provide a rationale for selecting a specific TKI for anticancer therapy in the clinic. Methods: Binding of rivoceranib to VEGFR-2 was determined on a Biacore T200. The affinity constant (KD) was derived from the association and dissociation rate constants. Inhibitory potency of rivoceranib and 10 FDA-approved reference inhibitors on kinase enzyme activity was determined using mobility shift assays (MSA) or immobilized metal ion affinity particle (IMAP) assays. The half-maximum inhibitory activity (IC50) of the 11 inhibitors on VEGFR-2 was determined in 10-point dose-response curves. The selectivity of the inhibitors was determined on 270 wild-type kinases at a fixed concentration of each inhibitor. Rivoceranib was tested at 10- and 100-times IC50 (160 nmol/L and 1.6 µmol/L). Reference inhibitors were tested at 1 µmol/L (35 to 1056-times IC50). Results: Rivoceranib had a KD of 3 nmol/L on VEGFR-2. In enzyme activity assays, rivoceranib had intermediate potency compared with the 10 reference inhibitors, with a VEGFR-2 kinase inhibition IC50 value of 16 nmol/L. Analysis of the residual activity of the panel of 270 kinases in the presence of rivoceranib or the reference inhibitors showed wide variation in selectivity for VEGFR-2, with rivoceranib identified as the most selective inhibitor (activity of 16 additional kinases inhibited by >50% at 1.6 µmol/L). Tivozanib, the most potent VEGFR-2 inhibitor, displayed greater than 50% inhibitory activity against more than 70 additional kinases. Sunitinib was identified as the least selective inhibitor included in this study, inhibiting 125 additional kinases by >50%. Conclusion: Variations in selectivity among TKIs with similar anti-VEGFR-2 potency can help explain differences in their clinical toxicity profiles, which may be partially due to variant inhibitory effects against TKIs other than VEGFR-2. This comparative biochemical analysis highlights the potential for rivoceranib to address clinical limitations associated with the poor selectivity of currently available VEGFR-2 inhibitors. Rivoceranib is under ongoing investigation as monotherapy and in combination with chemotherapy in various tumor types. Citation Format: Seong Jang, Bill Strickland, Lynda Finis, Jeffrey J. Koojiman, Janneke J. Melis, Guido J. Zaman, Jan V. Tornout. Comparative biochemical kinase activity analysis identifies rivoceranib as the most selective VEGFR-2 inhibitor compared with other TKIs with known activity against VEGFR-2. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4014.
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Kurihara, Hideyuki, and Kazuki Kujira. "Phlorotannins Derived From the Brown Alga Colpomenia bullosa as Tyrosinase Inhibitors." Natural Product Communications 16, no. 7 (July 2021): 1934578X2110213. http://dx.doi.org/10.1177/1934578x211021317.
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Tyrosinase catalyzes hydroxylation of L-tyrosine and dehydrogenation of L-DOPA in the melanin biosynthesis pathway. Tyrosinase inhibitors have potential use as cosmetic whitening agents and for preventing seafood deterioration. In this report, tyrosinase inhibitors extracted from brown alga Colpomenia bullosa (Scytosiphonaceae, Scytosiphonales) were investigated. Inhibitory principles were isolated from the extract and identified as phlorotannins, phloroglucinol (1), diphlorethol (2), triphlorethol C (3), which have not been isolated in a free form previously, and fucophlorethol C (4). Compounds 3 and 4 have not been reported previously as tyrosinase inhibitors. Triphlorethol C (3) was the most potent tyrosinase inhibitor among the phlorotannins isolated, whereas isomeric fucophlorethol C (4) displayed the weakest inhibitory activity. The results suggest that molecular structures of phlorotannins strongly affect their tyrosinase inhibitory activity.
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Pantoom, Supansa, Ingrid R. Vetter, Heino Prinz, and Wipa Suginta. "Potent Family-18 Chitinase Inhibitors." Journal of Biological Chemistry 286, no. 27 (April 29, 2011): 24312–23. http://dx.doi.org/10.1074/jbc.m110.183376.
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Six novel inhibitors of Vibrio harveyi chitinase A (VhChiA), a family-18 chitinase homolog, were identified by in vitro screening of a library of pharmacologically active compounds. Unlike the previously identified inhibitors that mimicked the reaction intermediates, crystallographic evidence from 14 VhChiA-inhibitor complexes showed that all of the inhibitor molecules occupied the outer part of the substrate-binding cleft at two hydrophobic areas. The interactions at the aglycone location are well defined and tightly associated with Trp-397 and Trp-275, whereas the interactions at the glycone location are patchy, indicating lower affinity and a loose interaction with two consensus residues, Trp-168 and Val-205. When Trp-275 was substituted with glycine (W275G), the binding affinity toward all of the inhibitors dramatically decreased, and in most structures two inhibitor molecules were found to stack against Trp-397 at the aglycone site. Such results indicate that hydrophobic interactions are important for binding of the newly identified inhibitors by the chitinase. X-ray data and isothermal microcalorimetry showed that the inhibitors occupied the active site of VhChiA in three different binding modes, including single-site binding, independent two-site binding, and sequential two-site binding. The inhibitory effect of dequalinium in the low nanomolar range makes this compound an extremely attractive lead compound for plausible development of therapeutics against human diseases involving chitinase-mediated pathologies.
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Kim, Min-Jeong, Sarita Pandit, and Jun-Goo Jee. "Discovery of Kinase and Carbonic Anhydrase Dual Inhibitors by Machine Learning Classification and Experiments." Pharmaceuticals 15, no. 2 (February 16, 2022): 236. http://dx.doi.org/10.3390/ph15020236.
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A multi-target small molecule modulator is advantageous for treating complicated diseases such as cancers. However, the strategy and application for discovering a multi-target modulator have been less reported. This study presents the dual inhibitors for kinase and carbonic anhydrase (CA) predicted by machine learning (ML) classifiers, and validated by biochemical and biophysical experiments. ML trained by CA I and CA II inhibitor molecular fingerprints predicted candidates from the protein-specific bioactive molecules approved or under clinical trials. For experimental tests, three sulfonamide-containing kinase inhibitors, 5932, 5946, and 6046, were chosen. The enzyme assays with CA I, CA II, CA IX, and CA XII have allowed the quantitative comparison in the molecules’ inhibitory activities. While 6046 inhibited weakly, 5932 and 5946 exhibited potent inhibitions with 100 nM to 1 μM inhibitory constants. The ML screening was extended for finding CAs inhibitors of all known kinase inhibitors. It found XMU-MP-1 as another potent CA inhibitor with an approximate 30 nM inhibitory constant for CA I, CA II, and CA IX. Differential scanning fluorimetry confirmed the direct interaction between CAs and small molecules. Cheminformatics studies, including docking simulation, suggest that each molecule possesses two separate functional moieties: one for interaction with kinases and the other with CAs.
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ALIAS, ZAZALI, and NORA ASYIKIN RAMLI. "PURIFICATION AND PARTIAL CHARACTERISATION OF A PROTEASE INHIBITOR FROM Mimosa diplotricha." Malaysian Applied Biology 51, no. 4 (October 31, 2022): 169–75. http://dx.doi.org/10.55230/mabjournal.v51i4.26.
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Search for inhibitors to insect proteases is one of many strategies to control pests. Previous work has demonstrated successful purification of effective inhibitors from plant origin. Thus, the current study attempted to purify protease inhibitors from locally available medicinal plants. The study demonstrated that the ethanolic extracts of Mimosa diplotricha leaves caused a significant 80% reduction in bovine trypsin activity. The inhibitory property of the proteinaceous nature of the extract was reconfirmed through qualitative analysis using the detection of trypsin inhibitors on the SDS-PAGE technique. The ammonium precipitated trypsin inhibitor was purified using Hi-Trap G25 and resolved into a single band with a molecular weight of approximately 20.8 kDa. By using the Dixon plot the competitive inhibitor has a Ki value of 2.16 × 10-4 mM. The purified protein inhibited the protease extract of Chrysomya megacephala at IC50 of 28 μg/mL. The results highlighted the presence of trypsin inhibitor in Mimosa diplotricha and its potential as a pest control agent.
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Du, Juan, Song Wang, Xinyue Zhang, Chang Liu, Yurou Zhang, and Hao Zhang. "The Inhibitory Mechanism of 7H-Pyrrolo[2,3-d]pyrimidine Derivatives as Inhibitors of P21-Activated Kinase 4 through Molecular Dynamics Simulation." Molecules 28, no. 1 (January 3, 2023): 413. http://dx.doi.org/10.3390/molecules28010413.
Full textAbstract:
The overexpression of p21-activated kinase 4 (PAK4) is associated with a variety of cancers. In this paper, the binding modes and inhibitory mechanisms of four 7H-pyrrolo[2,3-d]pyrimidine competitive inhibitors of PAK4 were investigated at the molecular level, mainly using molecular dynamics simulations and binding free energy calculations. The results show that the inhibitors had strong interactions with the hinge region, the β-sheets, and the residues with charged side chains around the 4-substituent. The terminal amino group of the inhibitor 5n was different from the other three, which could cause the enhancement of hydrogen bonds or electrostatic interactions formed with the surrounding residues. Thus, inhibitor 5n had the strongest inhibition capacity. The different halogen atoms on the 2-substituents of the inhibitors 5h, 5g, and 5e caused differences in the positions of the 2-benzene rings and affected the interactions of the hinge region. It also affected to some extent the orientations of the 4-imino groups and consequently their affinities for the surrounding charged residues. The combined results lead to the weakest inhibitory capacity of inhibitor 5e.
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Nasser, Rabab M., and Nora M. Masmali. "The effectiveness of Tamarindus Indica extracts as a metal corrosion inhibitor in various circumstances." Anti-Corrosion Methods and Materials 69, no. 3 (March 3, 2022): 224–33. http://dx.doi.org/10.1108/acmm-06-2021-2490.
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Purpose Plant development and use as green corrosion inhibitors are already recognized as one of the most environmentally friendly and effective protocols. In recent years, efforts have been made to find green corrosion inhibitors as an alternative to synthetic inhibitors for metals in acid medium. This paper aims to report the investigation of use of aqueous extracts of Tamarindus Indica as green inhibitors for corrosion of metals within different circumstances. Design/methodology/approach The use of Tamarindus Indica extracts (leaves, stem, fruit pulp and fruit husk) as corrosion inhibitors for mild steel and aluminum in different mediums (HCl, H2SO4, formic acid and citric acid) at different temperatures was investigated. Findings The inhibitory efficiency of Tamarindus Indica extracts increases with increasing concentration and decreases with increasing temperature. Langmuir is the adsorption isotherm, and the extract (inhibitor) is a mixed-type inhibitor (physisorption and chemisorption). Practical implications Tamarindus extracts (leaves, stem, fruit pulp and fruit husk) are effective inhibitors and can be used to protect metals from corrosion at different circumstances. Originality/value To the best of the authors’ knowledge, this is the first review that discusses the use of Tamarindus Indica extracts as corrosion inhibitors for metals.
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Kumar Dokka, Muni, Hemalatha K. P. J, and Siva Prasad Davuluri. "CHARACTERIZATION OF MONOHEADED TRYPSIN INHIBITORS FROM THE SEEDS OF ABELMOSCHUS MOSCHATUS L." Asian Journal of Pharmaceutical and Clinical Research 11, no. 12 (December 7, 2018): 459. http://dx.doi.org/10.22159/ajpcr.2018.v11i12.28735.
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Objective: The objective of the present study was to characterize the monoheaded trypsin inhibitors, Abelmoschus moschatus trypsin inhibitor-I (AMTI-I) and AMTI-II from the seeds of A. moschatus with respect to their specificity, mode of action, and active site residues.Methods: Standard methods were followed in determining inhibitory activities of monoheaded inhibitors. IC50 values and inhibitory constants (Ki) of AMTI-I and AMTI-II were determined. Studies on complex formation and chemical modification of inhibitors were performed.Results: AMTI-I and AMTI-II were found to be serpins, strongly active against trypsin, moderately active against porcine elastase, Staphylococcus aureus protease, and Aspergillus oryzae protease. AMTI-I and AMTI-II have shown non-competitive type of inhibition toward bovine trypsin with Ki values of inhibitors for trypsin found to be 0.25±0.02 nM and 0.22±0.06 nM, respectively. Complex studies revealed the formation of stable 1:1 complex of trypsin with both AMTI-I and AMTI-II. Chemical modification of the functional groups of the inhibitors by selective reagents indicated that arginine residues are essential for their trypsin inhibitory activities.Conclusion: Investigations on the specificity of protease inhibitors are important for understanding their physiological role, control mechanisms involved in the regulation of proteolysis in biological systems and mode of action.
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Wei, Jia, Ling Ma, Chenglong Li, Christopher R. Pierson, Jonathan L. Finlay, and Jiayuh Lin. "Targeting Upstream Kinases of STAT3 in Human Medulloblastoma Cells." Current Cancer Drug Targets 19, no. 7 (August 2, 2019): 571–82. http://dx.doi.org/10.2174/1568009618666181016165604.
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Background:Medulloblastoma is the most common malignant brain tumor in children. Despite improvement in overall survival rate, it still lacks an effective targeted treatment strategy. The Janus family of cytoplasmic tyrosine kinases (JAKs) and Src kinases, upstream protein kinases of signal transducer and activator of transcription 3 (STAT3), play important roles in medulloblastoma pathogenesis and therefore represent potential therapeutic targets.Methods:In this report, we examined the inhibitory efficacy of the JAK1/2 inhibitor, ruxolitinib, the JAK3 inhibitor, tofacitinib and two Src inhibitors, KX2-391 and dasatinib.Results:These small molecule drugs significantly reduce cell viability and inhibit cell migration and colony formation in human medulloblastoma cells in vitro. Src inhibitors have more potent efficacy than JAK inhibitors in inhibiting medulloblastoma cell migration ability. The Src inhibitors can inhibit both phosphorylation of STAT3 and Src while JAK inhibitors reduce JAK/STAT3 phosphorylation. We also investigated the combined effect of the Src inhibitor, dasatinib with cisplatin. The results show that dasatinib exerts synergistic effects with cisplatin in human medulloblastoma cells through the inhibition of STAT3 and Src.Conclusion:Our results suggest that the small molecule inhibitors of STAT3 upstream kinases, ruxolitinib, tofacitinib, KX2-391, and dasatinib could be novel and attractive candidate drugs for the treatment of human medulloblastoma.
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Ikari, Yuji, Eileen Mulvihill, and Stephen M. Schwartz. "α1-Proteinase Inhibitor, α1-Antichymotrypsin, and α2-Macroglobulin Are the Antiapoptotic Factors of Vascular Smooth Muscle Cells." Journal of Biological Chemistry 276, no. 15 (November 28, 2000): 11798–803. http://dx.doi.org/10.1074/jbc.m008503200.
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Serum depletion induces cell death. Whereas serum contains growth factors and adhesion molecules that are important for survival, serum is also likely to have antiapoptotic factor(s). We show here that the plasma proteinase inhibitors α1-proteinase inhibitor, α1-antichymotrypsin, and α2-macroglobulin function as critical antiapoptotic factors for human vascular smooth muscle cells. Cell survival was assured when serum-free medium was supplemented with any one or all of the above serine proteinase inhibitors. In contrast, the cells were sensitive to apoptosis when cultured in medium containing serum from which the proteinase inhibitors were removed. The antiapoptotic effect conferred by the proteinase inhibitors was proportional to proteinase inhibitory activity. Without proteinase inhibitors, the extracellular matrix was degraded, and cells could not attach to the matrix. Cell survival was dependent on the intact extracellular matrix. In the presence of the caspase inhibitor z-VAD, the cells detached but did not die. The activity of caspases was elevated without proteinase inhibitors; in contrast, caspases were not activated when medium was supplemented with one of the proteinase inhibitors. In conclusion, the plasma proteinase inhibitors prevent degradation of extracellular matrix by proteinases derived from cells. Presumably an intact cell-matrix interaction inhibits caspase activation and supports cell survival.
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Brewer, Jamie R., Sandra Harris, David Green, and Anaadriana Zakarija. "Significance of Factor VIII Inhibitors by ELISA in Patients with Hemophilia A." Blood 112, no. 11 (November 16, 2008): 3398. http://dx.doi.org/10.1182/blood.v112.11.3398.3398.
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Abstract Background: The Bethesda assay traditionally has been used to detect Factor VIII inhibitors in patients with Hemophilia A, but recent evidence suggests that it is not sensitive to all inhibitors, particularly non-inhibitory or low-titer antibodies. Methods: Patients with Hemophilia A without prior history of inhibitor were recruited. Study questionnaire collected demographic and clinical information, bleeding history and factor usage over the preceding 6 months. Functional status was assessed by the Hemophilia Activities List (HAL). Factor VIII inhibitor was assessed by both the Bethesda assay and Factor VIII inhibitor ELISA (GTI Diagnostics). T-test was performed to assess statistical significance. Results: Data is available for 26 patients, 19 severe, 2 moderate and 7 mild. All subjects had a negative Bethesda assay, but 10 (39%) had a detectable inhibitor by ELISA. 9/10 inhibitor patients had severe hemophilia, while one had mild hemophilia. In severe hemophiliacs, there were no differences in age, HIV status, CD4 count, Hepatitis C positivity or viral load between those with and those without inhibitors. Inhibitors were more frequent in those using plasma-derived concentrates 4/5 (80%), than in those using recombinant products 6/14 (43%), p=0.15. There was no difference in bleeding frequency or functional status in patients with or without inhibitors, although those with inhibitors had more frequent infusions.(Table). In patients on prophylaxis, those with inhibitors had a higher bleeding frequency compared to those without an inhibitor, (p =0.2). 11 patients were not on prophylaxis and had a higher bleeding frequency (p = 0.02) than patients on prophylaxis irrespective of inhibitor presence. However those with inhibitors required more factor doses per bleed compared to those without an inhibitor (4.4 vs. 1.5, p=0.16) even though the mean factor dose was the same (25.3 units/kg vs 25.2 units/kg). Conclusions: The Factor VIII ELISA assay detected inhibitors in 39 % of Hemophilia A patients who had undetectable inhibitors by standard Bethesda assay. This data suggests that these inhibitors may be clinically relevant, given that inhibitor patients who are not on prophylaxis require more doses of factor per bleeding event. Further study is necessary to determine mechanism and clinical significance of these Factor VIII inhibitors. Table. Characteristics of severe hemophilia patients with and without ELISA Factor VIII inhibitor All severe (n=19) Inhibitor (n=9) No inhibitor (n=10) Age 43.4 40.8 45.7 Plasma-derived factor 5 (26.3%) 4 (44.4%) 1 (10%) Total bleeds/6 months 8.6 8.1 9.0 Muscle bleeds/6 months 1.3 0.8 1.7 Joint bleeds/6 months 7.3 7.3 7.3 Factor infusions/6 months 50.9 57.2 45.2 On prophylaxis 8 (42%) 4 (44.4%) 4 (40%) Total bleeds/6 months 4.3 5.8 2.8 Not on prophylaxis 11 (58%) 5 (55.6%) 6 (60%) Total bleeds/6 months 11.7 10 13.2 Factor doses/bleed 2.9 4.4 1.5
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Juárez-Mercado, K. Eurídice, Fernando D. Prieto-Martínez, Norberto Sánchez-Cruz, Andrea Peña-Castillo, Diego Prada-Gracia, and José L. Medina-Franco. "Expanding the Structural Diversity of DNA Methyltransferase Inhibitors." Pharmaceuticals 14, no. 1 (December 27, 2020): 17. http://dx.doi.org/10.3390/ph14010017.
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Inhibitors of DNA methyltransferases (DNMTs) are attractive compounds for epigenetic drug discovery. They are also chemical tools to understand the biochemistry of epigenetic processes. Herein, we report five distinct inhibitors of DNMT1 characterized in enzymatic inhibition assays that did not show activity with DNMT3B. It was concluded that the dietary component theaflavin is an inhibitor of DNMT1. Two additional novel inhibitors of DNMT1 are the approved drugs glyburide and panobinostat. The DNMT1 enzymatic inhibitory activity of panobinostat, a known pan inhibitor of histone deacetylases, agrees with experimental reports of its ability to reduce DNMT1 activity in liver cancer cell lines. Molecular docking of the active compounds with DNMT1, and re-scoring with the recently developed extended connectivity interaction features approach, led to an excellent agreement between the experimental IC50 values and docking scores.
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Sõrmus, Tanel, Darja Lavogina, Erki Enkvist, Asko Uri, and Kaido Viht. "Deactivatable Bisubstrate Inhibitors of Protein Kinases." Molecules 27, no. 19 (October 8, 2022): 6689. http://dx.doi.org/10.3390/molecules27196689.
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Bivalent ligands, including bisubstrate inhibitors, are conjugates of pharmacophores, which simultaneously target two binding sites of the biomolecule. Such structures offer attainable means for the development of compounds whose ability to bind to the biological target could be modulated by an external trigger. In the present work, two deactivatable bisubstrate inhibitors of basophilic protein kinases (PKs) were constructed by conjugating the pharmacophores via linkers that could be cleaved in response to external stimuli. The inhibitor ARC-2121 incorporated a photocleavable nitrodibenzofuran-comprising β-amino acid residue in the structure of the linker. The pharmacophores of the other deactivatable inhibitor ARC-2194 were conjugated via reduction-cleavable disulfide bond. The disassembly of the inhibitors was monitored by HPLC-MS. The affinity and inhibitory potency of the inhibitors toward cAMP-dependent PK (PKAcα) were established by an equilibrium competitive displacement assay and enzyme activity assay, respectively. The deactivatable inhibitors possessed remarkably high 1–2-picomolar affinity toward PKAcα. Irradiation of ARC-2121 with 365 nm UV radiation led to reaction products possessing a 30-fold reduced affinity. The chemical reduction of ARC-2194 resulted in the decrease of affinity of over four orders of magnitude. The deactivatable inhibitors of PKs are valuable tools for the temporal inhibition or capture of these pharmacologically important enzymes.
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E, Jingwen, Ye Liu, Shanshan Guan, Zhijian Luo, Fei Han, Weiwei Han, Song Wang, and Hao Zhang. "How Different Substitution Positions of F, Cl Atoms in Benzene Ring of 5-Methylpyrimidine Pyridine Derivatives Affect the Inhibition Ability of EGFRL858R/T790M/C797S Inhibitors: A Molecular Dynamics Simulation Study." Molecules 25, no. 4 (February 18, 2020): 895. http://dx.doi.org/10.3390/molecules25040895.
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Lung cancer is the most frequent cause of cancer-related deaths worldwide, and mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are a common cause of non-small-cell lung cancers, which is a major subtype of lung cancers. Recently, a series of 5-methylpyrimidine-pyridinone derivatives have been designed and synthesized as novel selective inhibitors of EGFR and EGFR mutants. However, the binding-based inhibition mechanism has not yet been determined. In this study, we carried out molecular dynamic simulations and free-energy calculations for EGFR derivatives to fill this gap. Based on the investigation, the three factors that influence the inhibitory effect of inhibitors are as follows: (1) The substitution site of the Cl atom is the main factor influencing the activity through steric effect; (2) The secondary factors are repulsion between the F atom (present in the inhibitor) and Glu762, and the blocking effect of Lys745 on the phenyl ring of the inhibitor. (3) The two factors function synergistically to influence the inhibitory capacity of the inhibitor. The theoretical results of this study can provide further insights that will aid the design of oncogenic EGFR inhibitors with high selectivity.
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Muller, Florian, Selvi Kunnimalaiyaan, Parth Mangrolia, and Jill Olson. "Abstract 5913: TEAD1/4 inhibitors exhibit deeper biological impact and broader activity compared to TEAD1-only inhibitors in both monotherapy and combination without additional kidney toxicity." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5913. http://dx.doi.org/10.1158/1538-7445.am2024-5913.
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Abstract The TEAD transcription factors in association with the YAP/TAZ co-activators drive the expression of pro-proliferative and pro-oncogenic genes that underlies the transformed phenotype of many carcinomas. In addition, YAP-TEAD transcriptional activity is emerging as a major resistance mechanism for diverse precision oncology drugs, with the most extensive data for resistance to drugs targeting the MAPK pathway. There is a strong interest in generating inhibitors of YAP/TEAD transcriptional activity with TEAD palmitic acid site inhibitors having demonstrated encouraging pre-clinical activity and now clinical activity with confirmed objective responses with the TEAD1/2/3 inhibitor VT3989. However, the TEAD1-preferential inhibitor IK930 did not yield any objective responses but also showed a more favorable safety profile especially with respect to proteinuria. These contrasting clinical read-outs provide a good lead-in to a critical design challenge/question of TEAD palmitic acid site inhibitors: the optimization of inhibitory profile against the respective four TEAD paralogs (TEAD1-4). In depth bioinformatic analyses led Sporos investigators to conclude that while TEAD1 inhibition was a minimum requirement for anti-neoplastic activity, inhibition of other paralogs would be necessary for maximizing biological impact and a TEAD1/4 inhibitor would provide the best balance of anti-neoplastic activity and toxicity. Activity against TEAD2 was identified as counter-productive associated with a context-specific paradoxical stimulation of cell proliferation and tumor growth while activity against TEAD3 was flagged as a major driver of podocyte effacement and kidney toxicity. Here, we provide novel corroborating data supporting this selection of inhibitory profile. We provide an update on the pre-clinical efficacy and toxicology of SPR1, Sporos’s TEAD1/4 preferential inhibitor which favorably contrasts with other TEAD inhibitors such as the TEAD1/3/4 inhibitor VT3989 and the TEAD1 inhibitor VT103 and IK930 in both the monotherapy and combination setting. We show that 1) SPR1 displays broader and deeper cell-based activity and extends the utility of TEAD inhibitors outside of mesothelioma and NF2 mutants 2) SPR1 shows stronger activity than TEAD1-only inhibitors in combination with MAPK and EGFR inhibitors in vitro and in vivo 3) SPR1 does not cause proteinuria in mice; dogs or rats even above therapeutic doses 4) SPR1 does not show the context-specific stimulation of tumor growth in Lung PDX previously observed with VT3989 and other inhibitors that include TEAD2 in their profile. Taken together - the data suggests SPR1 is positioned to become a best-in-class TEAD palmitic acid site inhibitor with broad utility in both monotherapy and combination setting. Citation Format: Florian Muller, Selvi Kunnimalaiyaan, Parth Mangrolia, Jill Olson. TEAD1/4 inhibitors exhibit deeper biological impact and broader activity compared to TEAD1-only inhibitors in both monotherapy and combination without additional kidney toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5913.
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Tiyoula, Fereshteh Noroozi, Hassan Aryapour, and Mostafa Javaheri Moghadam. "Comparative study of the unbinding process of some HTLV-1 protease inhibitors using unbiased molecular dynamics simulations." PLOS ONE 17, no. 7 (July 14, 2022): e0263200. http://dx.doi.org/10.1371/journal.pone.0263200.
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The HTLV-1 protease is one of the major antiviral targets to overwhelm this virus. Several research groups have developed protease inhibitors, but none has been successful. In this regard, developing new HTLV-1 protease inhibitors to fix the defects in previous inhibitors may overcome the lack of curative treatment for this oncovirus. Thus, we decided to study the unbinding pathways of the most potent (compound 10, PDB ID 4YDF, Ki = 15 nM) and one of the weakest (compound 9, PDB ID 4YDG, Ki = 7900 nM) protease inhibitors, which are very structurally similar. We conducted 12 successful short and long simulations (totaling 14.8 μs) to unbind the compounds from two monoprotonated (mp) forms of protease using the Supervised Molecular Dynamics (SuMD) without applying any biasing force. The results revealed that Asp32 or Asp32′ in the two forms of mp state similarly exert powerful effects on maintaining both potent and weak inhibitors in the binding pocket of HTLV-1 protease. In the potent inhibitor’s unbinding process, His66′ was a great supporter that was absent in the weak inhibitor’s unbinding pathway. In contrast, in the weak inhibitor’s unbinding process, Trp98/Trp98′ by pi-pi stacking interactions were unfavorable for the stability of the inhibitor in the binding site. In our opinion, these results will assist in designing more potent and effective inhibitors for the HTLV-1 protease.
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Gao, Yinghong, Stephen P. Davies, Martin Augustin, Anna Woodward, Umesh A. Patel, Robert Kovelman, and Kevin J. Harvey. "A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery." Biochemical Journal 451, no. 2 (March 28, 2013): 313–28. http://dx.doi.org/10.1042/bj20121418.
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Despite the development of a number of efficacious kinase inhibitors, the strategies for rational design of these compounds have been limited by target promiscuity. In an effort to better understand the nature of kinase inhibition across the kinome, especially as it relates to off-target effects, we screened a well-defined collection of kinase inhibitors using biochemical assays for inhibitory activity against 234 active human kinases and kinase complexes, representing all branches of the kinome tree. For our study we employed 158 small molecules initially identified in the literature as potent and specific inhibitors of kinases important as therapeutic targets and/or signal transduction regulators. Hierarchical clustering of these benchmark kinase inhibitors on the basis of their kinome activity profiles illustrates how they relate to chemical structure similarities and provides new insights into inhibitor specificity and potential applications for probing new targets. Using this broad dataset, we provide a framework for assessing polypharmacology. We not only discover likely off-target inhibitor activities and recommend specific inhibitors for existing targets, but also identify potential new uses for known small molecules.
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Balzarini, J., and E. De Clercq. "The Thiocarboxanilides UC-10 and UC-781 Have an Additive Inhibitory Effect against Human Immunodeficiency Virus Type 1 Reverse Transcriptase and Replication in Cell Culture When Combined with other Antiretroviral Drugs." Antiviral Chemistry and Chemotherapy 8, no. 3 (June 1997): 197–204. http://dx.doi.org/10.1177/095632029700800303.
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The thiocarboxanilides represent a structural class of potent and selective human immunodeficiency virus type 1 (HIV-1)-specific reverse transcriptase (RT) inhibitors. Combinations of the clinical candidate thiocarboxanilides UC-10 (oxime ether derivative) and UC-781 (pentenyloxy ether derivative) with a variety of nucleoside RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs), two HIV protease inhibitors and one fusion/uncoating inhibitor were evaluated for their inhibitory effects on HIV-1 RT activity and HIV-1 replication in CEM cell cultures. The inhibitory activity of the NNRTIs including UC-10, UC-781, nevirapine, BHAR α-APA, 8-chloro-TIBO, MKC-442 and the quinoxaline HBY 097 against HIV-1 RT was highly dependent on the nature of the template/primer used in the HIV-1 RT reaction. However, fractionary inhibitory concentration (FIC) indexes for all drug concentrations evaluated in the combination experiments of UC-781 and the other NNRTIs fell within the range 0.5–1.5. This points to a predominantly additive effect of the thiocarboxanilides and other NNRTIs in the inhibition of HIV-1 RT. Similar FIC indexes were observed for the combination of UC-781 with the NRTI triphosphates AZT-TP, d4T-TP, ddCTP, ddATP and 3TC-TP and the NRTI diphosphate PMEApp against HIV-1 RT. All these drug combinations showed similar additive inhibitory effects on HIV-1 replication in cell culture. Also, the combinations of UC-10 or UC-781 with the protease inhibitors Ro31–8959/008 and ABT 84538.0 and the fusion/uncoating inhibitor bicyclam JM 3100 showed an additive effect (FIC within the 0.5–1.5 range). Thus, irrespective of the nature of the drugs, their combination with the thiocarboxanilides proved merely additive. In no case were antagonistic anti-HIV activity or increased cytotoxicity observed. In conclusion, thiocarboxanilides combined with a variety of clinically used anti-HIV agents result in additive anti-HIV activity.
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Rødland, Gro Elise, Sissel Hauge, Grete Hasvold, Lilli T. E. Bay, Tine T. H. Raabe, Mrinal Joel, and Randi G. Syljuåsen. "Differential Effects of Combined ATR/WEE1 Inhibition in Cancer Cells." Cancers 13, no. 15 (July 28, 2021): 3790. http://dx.doi.org/10.3390/cancers13153790.
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Inhibitors of WEE1 and ATR kinases are considered promising for cancer treatment, either as monotherapy or in combination with chemo- or radiotherapy. Here, we addressed whether simultaneous inhibition of WEE1 and ATR might be advantageous. Effects of the WEE1 inhibitor MK1775 and ATR inhibitor VE822 were investigated in U2OS osteosarcoma cells and in four lung cancer cell lines, H460, A549, H1975, and SW900, with different sensitivities to the WEE1 inhibitor. Despite the differences in cytotoxic effects, the WEE1 inhibitor reduced the inhibitory phosphorylation of CDK, leading to increased CDK activity accompanied by ATR activation in all cell lines. However, combining ATR inhibition with WEE1 inhibition could not fully compensate for cell resistance to the WEE1 inhibitor and reduced cell viability to a variable extent. The decreased cell viability upon the combined treatment correlated with a synergistic induction of DNA damage in S-phase in U2OS cells but not in the lung cancer cells. Moreover, less synergy was found between ATR and WEE1 inhibitors upon co-treatment with radiation, suggesting that single inhibitors may be preferable together with radiotherapy. Altogether, our results support that combining WEE1 and ATR inhibitors may be beneficial for cancer treatment in some cases, but also highlight that the effects vary between cancer cell lines.
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Lechner, Christian, Maren Flaßhoff, Hannes Falke, Lutz Preu, Nadége Loaëc, Laurent Meijer, Stefan Knapp, Apirat Chaikuad, and Conrad Kunick. "[b]-Annulated Halogen-Substituted Indoles as Potential DYRK1A Inhibitors." Molecules 24, no. 22 (November 13, 2019): 4090. http://dx.doi.org/10.3390/molecules24224090.
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Since hyperactivity of the protein kinase DYRK1A is linked to several neurodegenerative disorders, DYRK1A inhibitors have been suggested as potential therapeutics for Down syndrome and Alzheimer’s disease. Most published inhibitors to date suffer from low selectivity against related kinases or from unfavorable physicochemical properties. In order to identify DYRK1A inhibitors with improved properties, a series of new chemicals based on [b]-annulated halogenated indoles were designed, synthesized, and evaluated for biological activity. Analysis of crystal structures revealed a typical type-I binding mode of the new inhibitor 4-chlorocyclohepta[b]indol-10(5H)-one in DYRK1A, exploiting mainly shape complementarity for tight binding. Conversion of the DYRK1A inhibitor 8-chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one into a corresponding Mannich base hydrochloride improved the aqueous solubility but abrogated kinase inhibitory activity.
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Kubyshkin, A. V., and I. I. Fomochkina. "THE INFLUENCE OF INTRODUCTION OF PROTEINASE INHIBITORS ON EFFICIENCY FOR SUPPRESSION OF PROTEOLYTIC ACTIVATION OF PNEUMONIA." Fiziolohichnyĭ zhurnal 55, no. 1 (February 4, 2009): 43–48. http://dx.doi.org/10.15407/fz55.01.043.
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We studied the influence of a way of introduction proteinase inhibitors on efficiency of suppression of proteolysis activation during pneumonia. Comparative study of efficiency of proteases inhibition in experimental pneumonia has shown higher efficacy of local introduction of drugs. Intravenous and intraperitoneal introduction of proteinase inhibitors exhibited inhibitory effect of a smaller degree on local and systemic proteases activation, did not decrease an acute phase of response of a-1-protease inhibitor in comparison with endotracheal instillation of Contrycal and Ingiprol. The study has established that endotracheal introduction of proteinase inhibitors is the most effective for correction of the proteinase-inhibitor balance. It also helps to promote the activity proteinase-inhibitor, suppresses elastolytic activity, decreases cellular infiltration, reduces the concentration of proteins in bronco-alveolar lavage fluid that is connected with address delivery of drugs to the target organ creating a maximal concentration of drugs in affected area.