Articles de revues : « Inhibitors, Robustness »

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Fuentes, Miguel A., et David C. Krakauer. « The evolution of developmental patterning under genetic duplication constraints ». Journal of The Royal Society Interface 5, n^o 19 (26 juin 2007) : 237–45. http://dx.doi.org/10.1098/rsif.2007.1074.

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Of considerable interest are the evolutionary and developmental origins of complex, adaptive structures and the mechanisms that stabilize these structures. We consider the relationship between the evolutionary process of gene duplication and deletion and the stability of morphogenetic patterns produced by interacting activators and inhibitors. We compare the relative stability of patterns with a single activator and inhibitor (two-dimensional system) against a ‘redundant’ system with two activators or two inhibitors (three-dimensional system). We find that duplication events can both expand and contract the space of patterns. We study developmental robustness in terms of stochastic escape times from this space, also known as a ‘canalization potential’. We embed the output of pattern formation into an explicit evolutionary model of gene duplication, gene loss and variation in the steepness of the canalization potential. We find that under all constant conditions, the system evolves towards a preference for steep potentials associated with low phenotypic variability and longer lifespans. This preference leads to an overall decrease in the density of redundant genotypes as developmental robustness neutralizes the advantages of genetic robustness.

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Teixeira, Vanessa S., Suéllen P. H. Azambuja, Priscila H. Carvalho, Fátima A. A. Costa, Patricia R. Kitaka, Claudia Stekelgerb, Silvio R. Andrietta, Maria G. S. Andrietta et Rosana Goldbeck. « Robustness and Ethanol Production of Industrial Strains of Saccharomyces cerevisiae Using Different Sugarcane Bagasse Hydrolysates ». Journal of Applied Biotechnology 7, n^o 1 (7 mai 2019) : 23. http://dx.doi.org/10.5296/jab.v7i1.14599.

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Sugarcane bagasse is one of the main lignocellulosic raw materials used for the production of second-generation ethanol. Technological studies on fermentation processes have focused on the search for and development of more robust microorganisms that are able to produce bioethanol efficiently and are resistant to the main fermentation inhibitors. The purpose of this study was to evaluate the robustness and ethanol production of industrial strains of Saccharomyces cerevisiae using acid, alkaline, and enzymatic sugarcane bagasse hydrolysates. Hydrolysis was carried out to release fermentable sugars from sugarcane bagasse. Fermentations were performed in shake flasks containing sugarcane hydrolysates supplemented with 150 g L−1 glucose to evaluate the kinetic parameters of the reaction. Inhibitor tolerance was evaluated by incubating cells with different concentrations of inhibitors in 96-well plates. The biomass yield on substrate, ethanol yield on substrate, and ethanol productivity of the six strains were higher in 0.5% acid, 0.5% alkaline, and enzymatic hydrolysates (i.e., under milder conditions). The SA-1 (Santa Adélia-1) strain had a better performance in comparison with the other strains for its ability to produce ethanol in a very severe condition (7% acid hydrolysis) and for its robustness in growing at several inhibitor concentrations.

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Meeks, Shannon L., Alexander M. Sevy, John F. Healey, Wei Deng, P. Clint Spiegel et Renhao Li. « Cooperative Binding Of Anti-Factor VIII Inhibitors and Induced Conformational Change Detected By Hydrogen-Deuterium Exchange Mass Spectrometry ». Blood 122, n^o 21 (15 novembre 2013) : 1088. http://dx.doi.org/10.1182/blood.v122.21.1088.1088.

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Abstract The development of anti-factor VIII (fVIII) antibodies (inhibitors) is a significant complication in the management of patients with hemophilia A leading to significant increases in morbidity and treatment cost. Using a panel of anti-fVIII monoclonal antibodies to different epitopes on fVIII, we recently have shown that epitope specificity, inhibitor kinetics, and time to maximum inhibition are more important than inhibitor titer in predicting response to fVIII and the combination of fVIII and recombinant factor VIIa. Thus the ability to quickly map the epitope spectrum of patient plasma using a clinically feasible assay may fundamentally change how clinicians approach the treatment of high-titer inhibitor patients. To this end, we have characterized the binding epitopes of 4 monoclonal antibodies (MAbs) targeted against fVIII C2 domain by hydrogen-deuterium exchange coupled with liquid chromatography-mass spectrometry (HDX-MS). MAbs included both classical (inhibiting binding of fVIII to von Willebrand factor and phospholipid) and non-classical inhibitors (inhibiting activation of fVIII), which target separate regions of fVIII C2 domain and have distinct inhibitory mechanisms. HDX-MS analysis showed clear differences in binding patterns between classical and non-classical inhibitors, centering on the protruding hydrophobic loop at Met2199. The binding epitopes of classical and non-classical inhibitors mapped by HDX-MS agree well with previously reported ones characterized by structural studies and mutagenesis analysis. Classical and non-classical inhibitors could be distinguished by a limited subset of C2-derived peptides, simplifying analysis significantly. In addition, HDX-MS was able to detect subtle differences in binding patterns of various classical inhibitors, based on the HDX protection pattern around the hydrophobic loop at Leu2251. Interestingly, two MAbs, G99 and 3E6, exhibited an observable shift in HDX protection when bound to C2 as a ternary complex, as opposed to when bound individually, thus providing evidence for cooperative binding of these two MAbs (Figure 1). In summary, our results demonstrate the effectiveness and robustness of the HDX-MS method in the rapid epitope mapping of fVIII inhibitors. This method can be expanded to map epitopes of inhibitors against other domains of fVIII, potentially leading to a more personalized treatment of hemophilia A patients.Figure 1Figure 1. Disclosures: No relevant conflicts of interest to declare.

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Zhao, Junnan, Lu Zhu, Weineng Zhou, Lingfeng Yin, Yuchen Wang, Yuanrong Fan, Yadong Chen et Haichun Liu. « In silico Prediction of Inhibitory Constant of Thrombin Inhibitors Using Machine Learning ». Combinatorial Chemistry & ; High Throughput Screening 21, n^o 9 (21 janvier 2019) : 662–69. http://dx.doi.org/10.2174/1386207322666181220130232.

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Background: Thrombin is the central protease of the vertebrate blood coagulation cascade, which is closely related to cardiovascular diseases. The inhibitory constant Ki is the most significant property of thrombin inhibitors. Method: This study was carried out to predict Ki values of thrombin inhibitors based on a large data set by using machine learning methods. Taking advantage of finding non-intuitive regularities on high-dimensional datasets, machine learning can be used to build effective predictive models. A total of 6554 descriptors for each compound were collected and an efficient descriptor selection method was chosen to find the appropriate descriptors. Four different methods including multiple linear regression (MLR), K Nearest Neighbors (KNN), Gradient Boosting Regression Tree (GBRT) and Support Vector Machine (SVM) were implemented to build prediction models with these selected descriptors. Results: The SVM model was the best one among these methods with R2=0.84, MSE=0.55 for the training set and R2=0.83, MSE=0.56 for the test set. Several validation methods such as yrandomization test and applicability domain evaluation, were adopted to assess the robustness and generalization ability of the model. The final model shows excellent stability and predictive ability and can be employed for rapid estimation of the inhibitory constant, which is full of help for designing novel thrombin inhibitors.

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Avval, Zhila, Eslam Pourbashir, Mohammad Ganjali et Parviz Norouzi. « Application of genetic algorithm - multiple linear regressions to predict the activity of RSK inhibitors ». Journal of the Serbian Chemical Society 80, n^o 2 (2015) : 187–96. http://dx.doi.org/10.2298/jsc140523064a.

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This paper deals with developing a linear quantitative structure-activity relationship (QSAR) model for predicting the RSK inhibition activity of some new compounds. A dataset consisting of 62 pyrazino [1,2-?] indole, diazepino [1,2-?] indole, and imidazole derivatives with known inhibitory activities was used. Multiple linear regressions (MLR) technique combined with the stepwise (SW) and the genetic algorithm (GA) methods as variable selection tools was employed. For more checking stability, robustness and predictability of the proposed models, internal and external validation techniques were used. Comparison of the results obtained, indicate that the GA-MLR model is superior to the SW-MLR model and that it isapplicable for designing novel RSK inhibitors.

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Green, Keith D., Ankita Punetha, Caixia Hou, Sylvie Garneau-Tsodikova et Oleg V. Tsodikov. « Probing the Robustness of Inhibitors of Tuberculosis Aminoglycoside Resistance Enzyme Eis by Mutagenesis ». ACS Infectious Diseases 5, n^o 10 (21 août 2019) : 1772–78. http://dx.doi.org/10.1021/acsinfecdis.9b00228.

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Kremb, Stephan, Markus Helfer, Werner Heller, Dieter Hoffmann, Horst Wolff, Andrea Kleinschmidt, Sabine Cepok, Bernhard Hemmer, Jörg Durner et Ruth Brack-Werner. « EASY-HIT : HIV Full-Replication Technology for Broad Discovery of Multiple Classes of HIV Inhibitors ». Antimicrobial Agents and Chemotherapy 54, n^o 12 (27 septembre 2010) : 5257–68. http://dx.doi.org/10.1128/aac.00515-10.

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ABSTRACT HIV replication assays are important tools for HIV drug discovery efforts. Here, we present a full HIV replication system (EASY-HIT) for the identification and analysis of HIV inhibitors. This technology is based on adherently growing HIV-susceptible cells, with a stable fluorescent reporter gene activated by HIV Tat and Rev. A fluorescence-based assay was designed that measures HIV infection by two parameters relating to the early and the late phases of HIV replication, respectively. Validation of the assay with a panel of nine reference inhibitors yielded effective inhibitory concentrations consistent with published data and allowed discrimination between inhibitors of early and late phases of HIV replication. Finer resolution of the effects of reference drugs on different steps of HIV replication was achieved in secondary time-of-addition assays. The EASY-HIT assay yielded high Z′ scores (>0.9) and signal stabilities, confirming its robustness. Screening of the LOPAC1280 library identified 10 compounds (0.8%), of which eight were known to inhibit HIV, validating the suitability of this assay for screening applications. Studies evaluating anti-HIV activities of natural products with the EASY-HIT technology led to the identification of three novel inhibitory compounds that apparently act at different steps of HIV-1 replication. Furthermore, we demonstrate successful evaluation of plant extracts for HIV-inhibitory activities, suggesting application of this technology for the surveillance of biological extracts with anti-HIV activities. We conclude that the EASY-HIT technology is a versatile tool for the discovery and characterization of HIV inhibitors.

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Halim, Sobia Ahsan, Sumaira Jabeen, Ajmal Khan et Ahmed Al-Harrasi. « Rational Design of Novel Inhibitors of α-Glucosidase : An Application of Quantitative Structure Activity Relationship and Structure-Based Virtual Screening ». Pharmaceuticals 14, n^o 5 (19 mai 2021) : 482. http://dx.doi.org/10.3390/ph14050482.

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α-Glucosidase is considered a prime drug target for Diabetes Mellitus and its inhibitors are used to delay carbohydrate digestion for the treatment of diabetes mellitus. With the aim to design α-glucosidase inhibitors with novel chemical scaffolds, three folds ligand and structure based virtual screening was applied. Initially linear quantitative structure activity relationship (QSAR) model was developed by a molecular operating environment (MOE) using a training set of thirty-two known inhibitors, which showed good correlation coefficient (r2 = 0.88), low root mean square error (RMSE = 0.23), and cross-validated correlation coefficient r2 (q2 = 0.71 and RMSE = 0.31). The model was validated by predicting the biological activities of the test set which depicted r2 value of 0.82, indicating the robustness of the model. For virtual screening, compounds were retrieved from zinc is not commercial (ZINC) database and screened by molecular docking. The best docked compounds were chosen to assess their pharmacokinetic behavior. Later, the α-glucosidase inhibitory potential of the selected compounds was predicted by their mode of binding interactions. The predicted pharmacokinetic profile, docking scores and protein-ligand interactions revealed that eight compounds preferentially target the catalytic site of α-glucosidase thus exhibit potential α-glucosidase inhibition in silico. The α-glucosidase inhibitory activities of those Hits were predicted by QSAR model, which reflect good inhibitory activities of these compounds. These results serve as a guidelines for the rational drug design and development of potential novel anti-diabetic agents.

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Zhang, Meng, Yiwei Lai, Vladislav Krupalnik, Pengcheng Guo, Xiangpeng Guo, Jianguo Zhou, Yan Xu et al. « β-Catenin safeguards the ground state of mousepluripotency by strengthening the robustness of the transcriptional apparatus ». Science Advances 6, n^o 29 (juillet 2020) : eaba1593. http://dx.doi.org/10.1126/sciadv.aba1593.

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Mouse embryonic stem cells cultured with MEK (mitogen-activated protein kinase kinase) and GSK3 (glycogen synthase kinase 3) inhibitors (2i) more closely resemble the inner cell mass of preimplantation blastocysts than those cultured with SL [serum/leukemia inhibitory factor (LIF)]. The transcriptional mechanisms governing this pluripotent ground state are unresolved. Release of promoter-proximal paused RNA polymerase II (Pol2) is a multistep process necessary for pluripotency and cell cycle gene transcription in SL. We show that β-catenin, stabilized by GSK3 inhibition in medium with 2i, supplies transcriptional coregulators at pluripotency loci. This selectively strengthens pluripotency loci and renders them addicted to transcription initiation for productive gene body elongation in detriment to Pol2 pause release. By contrast, cell cycle genes are not bound by β-catenin, and proliferation/self-renewal remains tightly controlled by Pol2 pause release under 2i conditions. Our findings explain how pluripotency is reinforced in the ground state and also provide a general model for transcriptional resilience/adaptation upon network perturbation in other contexts.

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Ask, Magnus, Valeria Mapelli, Heidi Höck, Lisbeth Olsson et Maurizio Bettiga. « Engineering glutathione biosynthesis of Saccharomyces cerevisiae increases robustness to inhibitors in pretreated lignocellulosic materials ». Microbial Cell Factories 12, n^o 1 (2013) : 87. http://dx.doi.org/10.1186/1475-2859-12-87.

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Usman, Muhammad Shariq, Muhammad Shahzeb Khan, Gregg C. Fonarow, Stephen J. Greene, Tim Friede, Muthiah Vaduganathan, Gerasimos Filippatos, Andrew J. Stewart Coats, Stefan D. Anker et Javed Butler. « Robustness of outcomes in trials evaluating sodium–glucose co‐transporter 2 inhibitors for heart failure ». ESC Heart Failure 9, n^o 2 (13 janvier 2022) : 885–93. http://dx.doi.org/10.1002/ehf2.13785.

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Yao, Dunfan, Sheng Dong, Pixiang Wang, Tianhu Chen, Jin Wang, Zheng-Bo Yue et Yi Wang. « Robustness of Clostridium saccharoperbutylacetonicum for acetone-butanol-ethanol production : Effects of lignocellulosic sugars and inhibitors ». Fuel 208 (novembre 2017) : 549–57. http://dx.doi.org/10.1016/j.fuel.2017.07.004.

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Wang, Yanan, Peng Zhan, Lishu Shao, Lin Zhang et Yan Qing. « Effects of Inhibitors Generated by Dilute Phosphoric Acid Plus Steam-Exploded Poplar on Saccharomyces cerevisiae Growth ». Microorganisms 10, n^o 7 (19 juillet 2022) : 1456. http://dx.doi.org/10.3390/microorganisms10071456.

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The pretreatment of lignocellulosic biomass is important for efficient bioethanol conversion, but causes undesirable by-products that inhibit microbial growth, conversely affecting the bioconversion efficiency. In this study, the main inhibitors derived from dilute phosphoric acid plus steam-exploded poplar wood were identified as 0.22 g/L furfural, 3.63 g/L acetic acid, 0.08 g/L syringaldehyde, etc., indicating the green nature and low toxicity of the pretreatment process. The effects of the three typical inhibitors (furfural, acetic acid, and syringaldehyde) on Saccharomyces cerevisiae 1517RM growth were analyzed and shown to prolong the lag phase of microbial growth to different degrees. In all the inhibitor groups, the ergosterol secretion was boosted, indicating low cell membrane fluidity and robustness of the strain to an adverse environment. The cell electronegativity and morphology of S. cerevisiae 1517RM also changed under different growth conditions, which was helpful for monitoring the physicochemical properties of cells. Furfural, acetic acid, and syringaldehyde had a synergistic effect on each other, providing an important reference to improving the subsequent ethanol fermentation process.

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Martins, Lucas Sousa, Reinaldo W. A. Gonçalves, Joana J. S. Moraes, Cláudio Nahum Alves et José Rogério A. Silva. « Computational Analysis of Triazole-Based Kojic Acid Analogs as Tyrosinase Inhibitors by Molecular Dynamics and Free Energy Calculations ». Molecules 27, n^o 23 (23 novembre 2022) : 8141. http://dx.doi.org/10.3390/molecules27238141.

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Molecular docking, molecular dynamics (MD) simulations and the linear interaction energy (LIE) method were used here to predict binding modes and free energy for a set of 1,2,3-triazole-based KA analogs as potent inhibitors of Tyrosinase (TYR), a key metalloenzyme of the melanogenesis process. Initially, molecular docking calculations satisfactorily predicted the binding mode of evaluated KA analogs, where the KA part overlays the crystal conformation of the KA inhibitor into the catalytic site of TYR. The MD simulations were followed by the LIE method, which reproduced the experimental binding free energies for KA analogs with an r2 equal to 0.97, suggesting the robustness of our theoretical model. Moreover, the van der Waals contributions performed by some residues such as Phe197, Pro201, Arg209, Met215 and Val218 are responsible for the binding recognition of 1,2,3-triazole-based KA analogs in TYR catalytic site. Finally, our calculations provide suitable validation of the combination of molecular docking, MD, and LIE approaches as a powerful tool in the structure-based drug design of new and potent TYR inhibitors.

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Moreno, Antonio D., Antonella Carbone, Rosita Pavone, Lisbeth Olsson et Cecilia Geijer. « Evolutionary engineered Candida intermedia exhibits improved xylose utilization and robustness to lignocellulose-derived inhibitors and ethanol ». Applied Microbiology and Biotechnology 103, n^o 3 (29 novembre 2018) : 1405–16. http://dx.doi.org/10.1007/s00253-018-9528-x.

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Kwon, Yong-Jun, Auguste Genovesio, Nam Youl Kim, Hi Chul Kim, Sungyong Jung, Brigitte David-Watine, Ulf Nehrbass et Neil Emans. « High-Content Classification of Nucleocytoplasmic Import or Export Inhibitors ». Journal of Biomolecular Screening 12, n^o 5 (août 2007) : 621–27. http://dx.doi.org/10.1177/1087057107301319.

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Transcription factors of the nuclear factor κ B family are the paradigm for signaling dependent nuclear translocation and are ideally suited to analysis through image-based chemical genetic screening. The authors describe combining high-content image analysis with a compound screen to identify compounds affecting either nuclear import or export. Validation in silico and in vitro determined an EC50 for the nuclear export blocker leptomycin B of 2.4 ng/mL (4.4 nM). The method demonstrated high selectivity (Z′ >0.95), speed, and robustness in a screen of a compound collection. It identified the IκB protein kinase inhibitor BAY 11 7082 as an import inhibitor, the p38 mitogen-activated protein (MAP) kinase inhibitor PD98509 as an import enhancer, and phorbol ester as an export inhibitor. The results establish a robust method for identifying compounds regulating nucleocytoplasmic import or export and also implicate MAP kinases in nuclear import of nuclear factor κ B. ( Journal of Biomolecular Screening 2007:621-627)

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Mahgoub Mohamed, Hiba Hashim, Amna Bint Wahab Elrashid Mohammed Hussien et Ahmed Elsadig Mohammed Saeed. « QSAR and docking studies of 3, 5-dimethylpyrazole as potent inhibitors of Phosphodiesterase-4 ». Journal of Drug Delivery and Therapeutics 11, n^o 1-s (15 février 2021) : 86–93. http://dx.doi.org/10.22270/jddt.v11i1-s.4718.

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A quantitative structure-activity relationship (QSAR) study was performed to develop a model on a series of 3, 5-dimethylpyrazole containing furan moiety derivatives which exhibited considerable inhibitory activity against PDE4B. The obtained model has correlation coefficient (r) of 0.934, squared correlation coefficient (r2) of 0.872, and leave-one-out (LOO) cross-validation coefficient (Q2) value of 0.733. The predictive power of the developed model was confirmed by the external validation which has (r2) value of 0.812. These parameters confirm the stability and robustness of the model to predict the activity of a new designed set of 3,5-dimethyl-pyrazole derivatives (I-XV), results indicated that the compound III, V, XIII, and XV showed the strongest inhibition activity (IC50 = 0.2813, 0.5814, 0.6929, 0.6125μM, respectively) against PDE4B compared to the reference rolipram with (IC50=1.9μM). Molecular docking was performed on a new designed compound with PDE4B protein (3o0j). Docking results showed that compounds (X and IX) have high docking affinity of -36.2037 and -33.2888 kcal/mol respectively. Keywords: QSAR, molecular docking, pyrazole derivatives, PDE4 inhibitors, anti-inflammatory.

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Rachdi, Mustapha, Jules Waku, Hana Hazgui et Jacques Demongeot. « Entropy as a Robustness Marker in Genetic Regulatory Networks ». Entropy 22, n^o 3 (25 février 2020) : 260. http://dx.doi.org/10.3390/e22030260.

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Genetic regulatory networks have evolved by complexifying their control systems with numerous effectors (inhibitors and activators). That is, for example, the case for the double inhibition by microRNAs and circular RNAs, which introduce a ubiquitous double brake control reducing in general the number of attractors of the complex genetic networks (e.g., by destroying positive regulation circuits), in which complexity indices are the number of nodes, their connectivity, the number of strong connected components and the size of their interaction graph. The stability and robustness of the networks correspond to their ability to respectively recover from dynamical and structural disturbances the same asymptotic trajectories, and hence the same number and nature of their attractors. The complexity of the dynamics is quantified here using the notion of attractor entropy: it describes the way the invariant measure of the dynamics is spread over the state space. The stability (robustness) is characterized by the rate at which the system returns to its equilibrium trajectories (invariant measure) after a dynamical (structural) perturbation. The mathematical relationships between the indices of complexity, stability and robustness are presented in case of Markov chains related to threshold Boolean random regulatory networks updated with a Hopfield-like rule. The entropy of the invariant measure of a network as well as the Kolmogorov-Sinaï entropy of the Markov transition matrix ruling its random dynamics can be considered complexity, stability and robustness indices; and it is possible to exploit the links between these notions to characterize the resilience of a biological system with respect to endogenous or exogenous perturbations. The example of the genetic network controlling the kinin-kallikrein system involved in a pathology called angioedema shows the practical interest of the present approach of the complexity and robustness in two cases, its physiological normal and pathological, abnormal, dynamical behaviors.

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Ma, Yufang, Richard J. Stern, Michael S. Scherman, Varalakshmi D. Vissa, Wenxin Yan, Victoria Cox Jones, Fangqiu Zhang, Scott G. Franzblau, Walter H. Lewis et Michael R. McNeil. « Drug Targeting Mycobacterium tuberculosis Cell Wall Synthesis : Genetics of dTDP-Rhamnose Synthetic Enzymes and Development of a Microtiter Plate-Based Screen for Inhibitors of Conversion of dTDP-Glucose to dTDP-Rhamnose ». Antimicrobial Agents and Chemotherapy 45, n^o 5 (1 mai 2001) : 1407–16. http://dx.doi.org/10.1128/aac.45.5.1407-1416.2001.

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ABSTRACT An l-rhamnosyl residue plays an essential structural role in the cell wall of Mycobacterium tuberculosis. Therefore, the four enzymes (RmlA to RmlD) that form dTDP-rhamnose from dTTP and glucose-1-phosphate are important targets for the development of new tuberculosis therapeutics. M. tuberculosis genes encoding RmlA, RmlC, and RmlD have been identified and expressed inEscherichia coli. It is shown here that genes for only one isotype each of RmlA to RmlD are present in the M. tuberculosis genome. The gene for RmlB is Rv3464. Rv3264c was shown to encode ManB, not a second isotype of RmlA. Using recombinant RmlB, -C, and -D enzymes, a microtiter plate assay was developed to screen for inhibitors of the formation of dTDP-rhamnose. The three enzymes were incubated with dTDP-glucose and NADPH to form dTDP-rhamnose and NADP+ with a concomitant decrease in optical density at 340 nm (OD340). Inhibitor candidates were monitored for their ability to lower the rate of OD340change. To test the robustness and practicality of the assay, a chemical library of 8,000 compounds was screened. Eleven inhibitors active at 10 μM were identified; four of these showed activities against whole M. tuberculosis cells, with MICs from 128 to 16 μg/ml. A rhodanine structural motif was present in three of the enzyme inhibitors, and two of these showed activity against wholeM. tuberculosis cells. The enzyme assay was used to screen 60 Peruvian plant extracts known to inhibit the growth ofM. tuberculosis in culture; two extracts were active inhibitors in the enzyme assay at concentrations of less than 2 μg/ml.

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Xue, Liu et Zheng. « Application of the Movable Type Free Energy Method to the Caspase-Inhibitor BindingAffinity Study ». International Journal of Molecular Sciences 20, n^o 19 (29 septembre 2019) : 4850. http://dx.doi.org/10.3390/ijms20194850.

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Many studies have provided evidence suggesting that caspases not only contribute to the neurodegeneration associated with Alzheimer’s disease (AD) but also play essential roles in promoting the underlying pathology of this disease. Studies regarding the caspase inhibition draw researchers’ attention through time due to its therapeutic value in the treatment of AD. In this work, we apply the “Movable Type” (MT) free energy method, a Monte Carlo sampling method extrapolating the binding free energy by simulating the partition functions for both free-state and bound-state protein and ligand configurations, to the caspase-inhibitor binding affinity study. Two test benchmarks are introduced to examine the robustness and sensitivity of the MT method concerning the caspase inhibition complexing. The first benchmark employs a large-scale test set including more than a hundred active inhibitors binding to caspase-3. The second benchmark includes several smaller test sets studying the relative binding free energy differences for minor structural changes at the caspase-inhibitor interaction interfaces. Calculation results show that the RMS errors for all test sets are below 1.5 kcal/mol compared to the experimental binding affinity values, demonstrating good performance in simulating the caspase-inhibitor complexing. For better understanding the protein-ligand interaction mechanism, we then take a closer look at the global minimum binding modes and free-state ligand conformations to study two pairs of caspase-inhibitor complexes with (1) different caspase targets binding to the same inhibitor, and (2) different polypeptide inhibitors targeting the same caspase target. By comparing the contact maps at the binding site of different complexes, we revealed how small structural changes affect the caspase-inhibitor interaction energies. Overall, this work provides a new free energy approach for studying the caspase inhibition, with structural insight revealed for both free-state and bound-state molecular configurations.

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Lu, Ying, Yan-Fei Cheng, Xiu-Ping He, Xue-Na Guo et Bo-Run Zhang. « Improvement of robustness and ethanol production of ethanologenic Saccharomyces cerevisiae under co-stress of heat and inhibitors ». Journal of Industrial Microbiology & ; Biotechnology 39, n^o 1 (23 juin 2011) : 73–80. http://dx.doi.org/10.1007/s10295-011-1001-0.

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Campbell, Heather M., Kathy D. Boardman, Melanie A. Dodd et Dennis W. Raisch. « Pharmacoeconomic Analysis of Angiotensin-Converting Enzyme Inhibitors in Type 2 Diabetes : A Markov Model ». Annals of Pharmacotherapy 41, n^o 7-8 (juillet 2007) : 1101–10. http://dx.doi.org/10.1345/aph.1k074.

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Background: Prevention of cardiovascular disease (CVD) events by initiating an angiotensin-converting enzyme (ACE) inhibitor on diagnosis of type 2 diabetes may increase survival and decrease costs. Objective: To determine the incremental cost-effectiveness ratios of ACE inhibitor initiation in normoaIbuminuric, microalbuminuruc, and macroaIbuminuric patients with newly diagnosed type 2 diabetes. Methods: A cohort of patients with newly diagnosed type 2 diabetes was followed for 8 years in a Markov model. Clinical outcomes included CVD events, dialysis, all-cause mortality, and the composite endpoints of the 3 events. Probabilities and costs were obtained from the literature. One-way and two-way sensitivity analyses were conducted to test the robustness of the model. Results: Implementation of ACE inhibitor therapy on diagnosis of type 2 diabetes in normoalbuminuric and microalbuminuric patients is a dominant strategy (ie, more effective and less costly) across all outcomes. In macro-albuminuric patients, an additional $4,10 and $4.58 saves one life and avoids one composite endpoint, respectively; however, in these patients, not giving an ACE inhibitor is dominant for prevention of CVD events and dialysis. This is due to a 28.62% higher mortality rate in patients not receiving an ACE inhibitor. Thus, analysts of the composite endpoint shows that not giving an ACE inhibitor does not remain dominant. A limitation of our study is the inability to determine causality. Conclusions: If every newly diagnosed patient with type 2 diabetes in the US was prescribed an ACE inhibitor, our model shows that 68 314 CVD events would be averted, 46410 lives would be saved, and 48 people would be prevented from needing dialysis over 8 years. These findings suggest that ACE inhibitors prevent numerous events in patients with type 2 diabetes who are normoalbuminuric at diagnosis, in addition to those already identified as being at risk for CVD events.

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Veríssimo, Gabriel Corrêa, Valtair Severino dos Santos Junior, Philipe Oliveira Fernandes, Shoichi Ishida, Ryosuke Kojima, Yasushi Okuno, Jadson Castro Gertrudes et Vinicius Gonçalves Maltarollo. « GCN-Based Structure-Activity Relationship and DFT Studies of Staphylococcus aureus FabI Inhibitors ». International Journal of Quantitative Structure-Property Relationships 7, n^o 1 (1 janvier 2022) : 1–16. http://dx.doi.org/10.4018/ijqspr.313627.

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The enoyl-[acyl-carrier-protein] reductase (FabI) is an important enzyme in the fatty acid metabolism of Gram-positive bacteria, such as Staphylococcus aureus. FabI is also a potential target for the development of novel antibacterials. Several machine learning-driven studies were reported to develop FabI inhibitors, describing robust and predictive models. Herein, the authors applied the kGCN, a graph convolutional network framework, to generate classification models to select potential S. aureus FabI inhibitors. The most predictive model showed robustness for both active and inactive class prediction, according to statistical validation. Finally, the chemical interpretation of the model was consistent with prior experimental and theoretical works. The SAR analysis highlighted the importance of the occupation of hydrophobic pockets and polar interactions with Tyr-156 and NADPH cofactor present in the FabI catalytic site by potential inhibitors. A density functional theory study endorsed the SAR, where the electrostatic surfaces were consistent with the expected interactions with the pocket.

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Rowinsky, Eric K., Agne Paner, Jesus G. Berdeja, Claudia Paba-Prada, Parameswaran Venugopal, Kimmo Porkka, Joachim Gullbo et al. « Phase 1 study of the protein deubiquitinase inhibitor VLX1570 in patients with relapsed and/or refractory multiple myeloma ». Investigational New Drugs 38, n^o 5 (3 mars 2020) : 1448–53. http://dx.doi.org/10.1007/s10637-020-00915-4.

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Summary This phase 1 study sought to characterize the safety, tolerability, and pharmacokinetic behavior of VLX1570, a small molecule inhibitor of the deubiquitinases (DUBs) that remove sterically bulky ubiquitin chains from proteins during processing in the19S regulatory subunit of the proteasome, in patients with relapsed and refractory multiple myeloma (MM). Fourteen patients were treated with escalating doses of VLX1570 ranging from 0.05 to 1.2 mg/kg as a brief intravenous (IV) infusion on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Due to its poor aqueous solubility, VLX1570 was formulated in polyethylene glycol, polyoxyethylated castor oil, and polysorbate 80 and administered as a brief intravenous (IV) infusion via a central venous catheter. Anti-myeloma effects were noted at doses at or above 0.6 mg/kg, however, two patients treated at the 1.2 mg/kg dose level experienced severe, abrupt, and progressive respiratory insufficiency, which was associated with diffuse pulmonary infiltrates on imaging studies, similar to those rarely noted with bortezomib and other inhibitors of the 20S proteasome, culminating in death. Although the contribution of VLX1570’s formulation to the pulmonary toxicity could not be ruled out, the severity and precipitous nature of the toxicity and the steep relationship between dose and toxicity, the study was discontinued. Despite the severe pulmonary toxicity noted with VLX1570, efforts directed at identifying DUB inhibitors with greater therapeutic indices appear warranted based on the unique mechanism of action, robustness of preclinical antitumor activity, and activity of the DUB inhibitors in MM resistant to PIs targeting the 20S proteasome subunit.

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Sarkar, Sampa, et Dhiman Sarkar. « Potential Use of Nitrate Reductase as a Biomarker for the Identification of Active and Dormant Inhibitors of Mycobacterium tuberculosis in a THP1 Infection Model ». Journal of Biomolecular Screening 17, n^o 7 (9 mai 2012) : 966–73. http://dx.doi.org/10.1177/1087057112445485.

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The development of a macrophage-based, antitubercular high-throughput screening system could expedite discovery programs for identifying novel inhibitors. In this study, the kinetics of nitrate reduction (NR) by Mycobacterium tuberculosis during growth in Thp1 macrophages was found to be almost parallel to viable bacilli count. NR in the culture medium containing 50 mM of nitrate was found to be optimum on the fifth day after infection with M. tuberculosis. The signal-to-noise (S/N) ratio and Z-factor obtained from this macrophage-based assay were 5.4 and 0.965, respectively, which confirms the robustness of the assay protocol. The protocol was further validated by using standard antitubercular inhibitors such as rifampicin, isoniazid, streptomycin, ethambutol, and pyrazinamide, added at their IC90 value, on the day of infection. These inhibitors were not able to kill the bacilli when added to the culture on the fifth day after infection. Interestingly, pentachlorophenol and rifampicin killed the bacilli immediately after addition on the fifth day of infection. Altogether, this assay protocol using M. tuberculosis–infected Thp-1 macrophages provides a novel, cost-efficient, robust, and easy-to-perform screening platform for the identification of both active and hypoxic stage-specific inhibitors against tuberculosis.

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Mens, Helene, Lasse Fjordside, Jannik Fonager et Jan Gerstoft. « Emergence of the G118R Pan-Integrase Resistance Mutation as a Result of Low Compliance to a Dolutegravir-Based cART ». Infectious Disease Reports 14, n^o 4 (22 juin 2022) : 501–4. http://dx.doi.org/10.3390/idr14040053.

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HIV-1 resistance towards integrase inhibitors is a potential threat of the success of HIV-1 combination treatment. G118R is a rare drug resistance mutation conferring pan-integrase resistance. Here, we describe the occurrence of G118R in a HIV-1 subtype-B-positive individual with major compliance problems, detected while the patient was on dolutegravir-based cART. We speculate the pre-selection of M184I/V aided the occurrence of G118R in this case, and discuss the robustness of dolutegravir-based therapies.

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Darling, H. S., et Alok Gupta. « Immune checkpoint inhibitor – antiangiogenic drugs combination in treatment-naïve metastatic clear cell renal cell carcinoma : Why should immunotherapy have all the fun ! » International Journal of Molecular & ; Immuno Oncology 5 (21 janvier 2020) : 1–7. http://dx.doi.org/10.25259/ijmio_23_2019.

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Clear cell histology is the most common subtype of renal cell carcinoma (RCC). Immune dysregulation and angiogenic pathways are the main drivers of the pathophysiology of RCC. The prognosis of metastatic RCC has very steadily improved from the era of interferon-alpha to tyrosine kinase inhibitors (TKIs) and then with immune checkpoint inhibitors (IOs). The safety and efficacy of both TKIs and IOs as well as the dire unmet need of further improvement in survival has unfolded the feasibility of successful conduction of IO based combination therapy trials. This has led to the approval of IO-IO and IO-TKI combinations, altering the treatment algorithm altogether once again. In this review, we are trying to look at the robustness of IO–antiangiogenic drugs combination data in upfront setting and its real-life application.

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Alquicer, Glenda, David Sedlák, Youngjoo Byun, Jiří Pavlíček, Marigo Stathis, Camilo Rojas, Barbara Slusher, Martin G. Pomper, Petr Bartůněk et Cyril Bařinka. « Development of a High-Throughput Fluorescence Polarization Assay to Identify Novel Ligands of Glutamate Carboxypeptidase II ». Journal of Biomolecular Screening 17, n^o 8 (29 juin 2012) : 1030–40. http://dx.doi.org/10.1177/1087057112451924.

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Glutamate carboxypeptidase II (GCPII) is an important target for therapeutic and diagnostic interventions aimed at prostate cancer and neurologic disorders. Here we describe the development and optimization of a high-throughput screening (HTS) assay based on fluorescence polarization (FP) that facilitates the identification of novel scaffolds inhibiting GCPII. First, we designed and synthesized a fluorescence probe based on a urea-based inhibitory scaffold covalently linked to a Bodipy TMR fluorophore (TMRGlu). Next, we established and optimized conditions suitable for HTS and evaluated the assay robustness by testing the influence of a variety of physicochemical parameters (e.g., pH, temperature, time) and additives. Using known GCPII inhibitors, the FP assay was shown to be comparable to benchmark assays established in the field. Finally, we evaluated the FP assay by HTS of a 20 000–compound library. The novel assay presented here is robust, highly reproducible (Z′ = 0.82), inexpensive, and suitable for automation, thus providing an excellent platform for HTS of small-molecule libraries targeting GCPII.

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Zhong, Ping, Zhiwen Lu, Zhangyu Li, Tianxiao Li, Qing Lan, Jianmin Liu, Zhanxiang Wang, Sifang Chen et Qinghai Huang. « Effect of Renin-Angiotensin-Aldosterone System Inhibitors on the Rupture Risk Among Hypertensive Patients With Intracranial Aneurysms ». Hypertension 79, n^o 7 (juillet 2022) : 1475–86. http://dx.doi.org/10.1161/hypertensionaha.122.18970.

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Background: Mounting experimental evidence supports the concept that the RAAS (renin-angiotensin-aldosterone system) is involved in the pathogenesis of intracranial aneurysm rupture. However, whether RAAS inhibitors could reduce the rupture risk of intracranial aneurysms remains unclear. Methods: We performed a chart review of a multicenter, prospectively maintained database of 3044 hypertensive patients with intracranial aneurysms from 20 medical centers in China. The patients were separated into ruptured and unruptured groups. Univariable and multivariable logistical regression analyses were performed to determine the association between the use of RAAS inhibitors and the rupture risk. Sensitivity analyses and subgroup analyses were performed to verify the robustness of the results. Results: In multivariable analyses, female sex, passive smoking, uncontrolled, or unmonitored hypertension, use of over 2 antihypertensive medications, RAAS inhibitors use, antihyperglycemic agents use, hyperlipidemia, ischemic stroke, and aneurysmal location were independently associated with the rupture risk. The use of RAAS inhibitors was significantly associated with a reduced rupture risk compared with the use of non-RAAS inhibitors (odds ratio, 0.490 [95% CI, 0.402–0.597]; P =0.000). Compared with the use of non-RAAS inhibitors, the use of ACE (angiotensin-converting enzyme) inhibitors (odds ratio, 0.559 [95% CI, 0.442–0.709]; P =0.000) and use of ARBs (angiotensin receptor blockers; odds ratio, 0.414 [95% CI, 0.315–0.542]; P =0.000) were both significantly associated with a reduced rupture risk. The negative association of the rupture risk with RAAS inhibitors was consistent across 3 analyzed data and the predefined subgroups (including controlled hypertension). Conclusions: The use of RAAS inhibitors was significantly associated with a decreased rupture risk independent of blood pressure control among hypertensive patients with intracranial aneurysms.

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Berzas Nevado, Juan José, María Jesús Villaseñor Llerena, Carmen Guiberteau Cabanillas, Virginia Rodríguez Robledo et Sierra Buitrago. « Sensitive capillary GC-MS-SIM determination of selective serotonin reuptake inhibitors : Reliability evaluation by validation and robustness study ». Journal of Separation Science 29, n^o 1 (janvier 2006) : 103–13. http://dx.doi.org/10.1002/jssc.200500119.

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Mittal, Anshika, Ritu Arora et Rita Kakkar. « Pharmacophore modeling, 3D-QSAR and molecular docking studies of quinazolines and aminopyridines as selective inhibitors of inducible nitric oxide synthase ». Journal of Theoretical and Computational Chemistry 18, n^o 01 (février 2019) : 1950002. http://dx.doi.org/10.1142/s0219633619500020.

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Pharmacophore modeling and 3D-Quantitative Structure Activity Relationship (3D-QSAR) studies have been performed on a dataset of thirty-two quinazoline and aminopyridine derivatives to get an insight into the important structural features required for binding to inducible nitric oxide synthase (iNOS). A four-point CPH (Common Pharmacophore Hypothesis), AHPR.29, with a hydrogen bond acceptor, hydrophobic group, positively charged ionizable group and an aromatic ring, has been obtained as the best pharmacophore model. Satisfactory statistical parameters of correlation ([Formula: see text]) and cross-validated ([Formula: see text]) correlation coefficients, 0.9288 and 0.6353, respectively, show high robustness and good predictive ability of our selected model. The contour maps have been developed from this model and the analysis has provided an interpretable explanation of the effect that various features and substituents have on the potency and selectivity of inhibitors towards iNOS. Docking studies have also been performed in order to analyze the interactions between the enzyme and the inhibitors. Our proposed model can thus be further used for screening a large database of compounds and design new iNOS inhibitors.

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Ghasemi, Jahan B., et Somayeh Pirhadi. « Docking alignment-3D-QSAR of a new class of potent and non-chiral indole-3-carboxamide-based renin inhibitors ». Collection of Czechoslovak Chemical Communications 76, n^o 12 (2011) : 1447–69. http://dx.doi.org/10.1135/cccc2011070.

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Using generated conformations from docking analysis by CDOCKER algorithm, some 3D-QSAR models; CoMFA region focusing (CoMFA-RF) and CoMSIA have been created on a series of a new class of potent and non-chiral renin inhibitors. The satisfactory predictions were obtained by CoMFA-RF and CoMSIA based on docking alignment in comparison to CoMFA. Robustness and predictability of the models were further verified by using the test set, cross validation (leave one out and leave ten out), bootstrapping, and progressive scrambling. All-orientation search (AOS) strategy was used to acquire the best orientation and minimize the effect of the initial orientation of aligned compounds. The results of 3D-QSAR models are in agreement with docking results. Moreover, the resulting 3D CoMFA-RF/ CoMSIA contour maps and corresponding models were applied to design new and more active inhibitors.

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Tutone, Marco, Beatrice Pecoraro et Anna M. Almerico. « Investigation on Quantitative Structure-Activity Relationships of 1,3,4-Oxadiazole Derivatives as Potential Telomerase Inhibitors ». Current Drug Discovery Technologies 17, n^o 1 (17 avril 2020) : 79–86. http://dx.doi.org/10.2174/1570163815666180724113208.

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Background:Telomerase, a reverse transcriptase, maintains telomere and chromosomes integrity of dividing cells, while it is inactivated in most somatic cells. In tumor cells, telomerase is highly activated, and works in order to maintain the length of telomeres causing immortality, hence it could be considered as a potential marker to tumorigenesis.A series of 1,3,4-oxadiazole derivatives showed significant broad-spectrum anticancer activity against different cell lines, and demonstrated telomerase inhibition.Methods:This series of 24 N-benzylidene-2-((5-(pyridine-4-yl)-1,3,4-oxadiazol-2yl)thio)acetohydrazide derivatives as telomerase inhibitors has been considered to carry out QSAR studies. The endpoint to build QSAR models is determined by the IC50 values for telomerase inhibition, i.e., the concentration (μM) of inhibitor that produces 50% inhibition. These values were converted to pIC50 (- log IC50) values. We used the most common and transparent method, where models are described by clearly expressed mathematical equations: Multiple Linear Regression (MLR) by Ordinary Least Squares (OLS).Results:Validated models with high correlation coefficients were developed. The Multiple Linear Regression (MLR) models, by Ordinary Least Squares (OLS), showed good robustness and predictive capability, according to the Multi-Criteria Decision Making (MCDM = 0.8352), a technique that simultaneously enhances the performances of a certain number of criteria. The descriptors selected for the models, such as electrotopological state (E-state) descriptors, and extended topochemical atom (ETA) descriptors, showed the relevant chemical information contributing to the activity of these compounds.Conclusion:The results obtained in this study make sure about the identification of potential hits as prospective telomerase inhibitors.

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Wong, Camilla L., Nick Bansback, Philip E. Lee et Aslam H. Anis. « Cost-Effectiveness : Cholinesterase Inhibitors and Memantine in Vascular Dementia ». Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 36, n^o 6 (novembre 2009) : 735–39. http://dx.doi.org/10.1017/s0317167100008350.

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Background:Several randomized controlled trials of cholinesterase inhibitors and memantine in mild to moderate vascular dementia have demonstrated the efficacy of these treatments. However, given these drugs incur considerable cost, the economic argument for their use is less clear.Objective:To determine the incremental cost-effectiveness of cholinesterase inhibitors and memantine for mild to moderate vascular dementia.Design:A decision analysis model using a 24-28 week time horizon was developed. Outcomes of cholinesterase inhibitors and memantine and probabilities of adverse events were extracted from a systematic review. Costs of adverse events, medications, and physician visits were obtained from local estimates. Robustness was tested with probabilistic sensitivity analysis using a Monte Carlo simulation.Interventions:Donepezil 5 mg daily, donepezil 10 mg daily, galantamine 16-24 mg daily, rivastigmine flexible dosing up to 6 mg twice daily, or memantine 10 mg twice daily versus standard care.Main Outcome Measures:Incremental cost-effectiveness ratio (ICER) expressed as cost per unit decrease in the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) subscale.Results:Donepezil 10 mg daily was found to be the most cost-effective treatment with an ICER of $400.64 (95%CI, $281.10-$596.35) per unit decline in the ADAS-cog subscale. All other treatments were dominated by donepezil 10 mg, that is, more costly and less effective.Conclusion:From a societal perspective, treatment with cholinesterase inhibitors or memantine was more effective but also more costly than standard care for mild to moderate vascular dementia. The donepezil 10 mg strategy was the most cost-effective and also dominated the other alternatives.

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Niyomrattanakit, Pornwaratt, Siti Nurdiana Abas, Chin Chin Lim, David Beer, Pei-Yong Shi et Yen-Liang Chen. « A Fluorescence-Based Alkaline Phosphatase–Coupled Polymerase Assay for Identification of Inhibitors of Dengue Virus RNA-Dependent RNA Polymerase ». Journal of Biomolecular Screening 16, n^o 2 (10 janvier 2011) : 201–10. http://dx.doi.org/10.1177/1087057110389323.

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The flaviviral RNA-dependent RNA polymerase (RdRp) is an attractive drug target. To discover new inhibitors of dengue virus RdRp, the authors have developed a fluorescence-based alkaline phosphatase–coupled polymerase assay (FAPA) for high-throughput screening (HTS). A modified nucleotide analogue (2′-[2-benzothiazoyl]-6′-hydroxybenzothiazole) conjugated adenosine triphosphate (BBT-ATP) and 3′UTR-U30 RNA were used as substrates. After the polymerase reaction, treatment with alkaline phosphatase liberates the BBT fluorophore from the polymerase reaction by-product, BBTPPi, which can be detected at excitation and emission wavelengths of 422 and 566 nm, respectively. The assay was evaluated by examining the time dependency, assay reagent effects, reaction kinetics, and signal stability and was validated with 3′dATP and an adenosine-nucleotide triphosphate inhibitor, giving IC50 values of 0.13 µM and 0.01 µM, respectively. A pilot screen of a diverse compound library of 40,572 compounds at 20 µM demonstrated good performance with an average Z factor of 0.81. The versatility and robustness of FAPA were evaluated with another substrate system, BBT-GTP paired with 3′UTR-C30 RNA. The FAPA method presented here can be readily adapted for other nucleotide-dependent enzymes that generate PPi.

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Romero, Celeste, Lester J. Lambert, Douglas J. Sheffler, Laurent J. S. De Backer, Dhanya Raveendra-Panickar, Maria Celeridad, Stefan Grotegut et al. « A cellular target engagement assay for the characterization of SHP2 (PTPN11) phosphatase inhibitors ». Journal of Biological Chemistry 295, n^o 9 (17 janvier 2020) : 2601–13. http://dx.doi.org/10.1074/jbc.ra119.010838.

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The nonreceptor protein-tyrosine phosphatase (PTP) SHP2 is encoded by the proto-oncogene PTPN11 and is a ubiquitously expressed key regulator of cell signaling, acting on a number of cellular processes and components, including the Ras/Raf/Erk, PI3K/Akt, and JAK/STAT pathways and immune checkpoint receptors. Aberrant SHP2 activity has been implicated in all phases of tumor initiation, progression, and metastasis. Gain-of-function PTPN11 mutations drive oncogenesis in several leukemias and cause developmental disorders with increased risk of malignancy such as Noonan syndrome. Until recently, small molecule-based targeting of SHP2 was hampered by the failure of orthosteric active-site inhibitors to achieve selectivity and potency within a useful therapeutic window. However, new SHP2 allosteric inhibitors with excellent potency and selectivity have sparked renewed interest in the selective targeting of SHP2 and other PTP family members. Crucially, drug discovery campaigns focusing on SHP2 would greatly benefit from the ability to validate the cellular target engagement of candidate inhibitors. Here, we report a cellular thermal shift assay that reliably detects target engagement of SHP2 inhibitors. Using this assay, based on the DiscoverX InCell Pulse enzyme complementation technology, we characterized the binding of several SHP2 allosteric inhibitors in intact cells. Moreover, we demonstrate the robustness and reliability of a 384-well miniaturized version of the assay for the screening of SHP2 inhibitors targeting either WT SHP2 or its oncogenic E76K variant. Finally, we provide an example of the assay's ability to identify and characterize novel compounds with specific cellular potency for either WT or mutant SHP2.

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Kassenova, Zh. « Residual chemical analysis of amines used as corrosion inhibitors ». Bulletin of the Innovative University of Eurasia 80, n^o 4 (25 décembre 2020) : 109–14. http://dx.doi.org/10.37788/2020-4/109-114.

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Main problem: Presence of acidic chemicals such as carbon dioxide and hydrogen sulphide, composition of production fluids triggers corrosion. Corrosion in oil and gas industry leads to deterioration of equipment since most of equipment is made of metal alloys. Application of inhibitors is one of the corrosion mitigation methods that needs to be controlled because it is important to identify optimal concentration of the chemicals in production fluids.Residual chemical analysis plays an important rolein identifying the appropriate dosage of corrosion inhibitors and its correction. It is imperative to find the most optimal concentration of amines due to the fact that both overdose and underdose could lead to equipment deterioration. The chemical analysis is hindered by complexity of mixtures that are applied in petroleum industry. Purpose: The main purpose of this article is to find out the most effective method of residual chemical analysis for inhibitors used against sweet and sour corrosion by studying and analyzing corresponding literature review. The analysis should be carried out with robust, sensitive, and accurate instrumentation. Methods :Theoretical study of composition and mechanism of amines used in oil and gas industry as corrosion inhibitors and selection of appropriate instrumental analytical techniques for the residual analysis. Results and their importance: After careful studying and consideration of modern instrumental analytical techniques the most optimal and efficient method in terms of robustness, time saving and cost was selected. Ion chromatography is an adequate method to carry out residual chemical analysis for amines that are used as inhibitors in oil and gas industry to prevent sweet and sour corrosion.

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Pham-the, Hai, et Huong Le-thi-thu. « INTEGRATING STRUCTURE AND LIGAND-BASED APPROACHES FOR MODELLING THE HISTONE DEACETYLASE INHIBITION ACTIVITY OF HYDROXAMIC ACID DERIVATIVES ». Asian Journal of Pharmaceutical and Clinical Research 11, n^o 2 (1 février 2018) : 198. http://dx.doi.org/10.22159/ajpcr.2018.v11i2.22995.

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Objective: Structure and ligand-based drug design approaches have be been integrated to accurately predict the inhibition activity of hydroxamic acid (HA) derivatives against the histone deacetylase-2 enzyme (HDAC2).Methods: The “active conformations” of the ligands in the binding site of the enzyme were determined by docking assays. More than 1000 0–3 dimensional molecular descriptors included in Dragon package were calculated and utilized for developing quantitative structure-activity relationship (QSAR) models through a multiple linear regression approach coupled with the genetic algorithm (GA-MLR).Results: The final model obtained showed suitable robustness and stability, with low correlation between descriptors and good predictive power. QSAR model was then used for screening bioactivity from a series of 36 novel HAs and found five candidates with very good bioactivity (half maximal inhibitory concentration<0.1 μM). Docking experiment revealed the binding mode of these compounds into the active site of HDAC2. Drug-likeness and toxicity profiles of the compounds were checked through chemoinformatics tools.Conclusion: The results from this study can lead to rational design and synthesis of highly selective and potent HDAC2 inhibitors.

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Pattenden, Samantha G., Jeremy M. Simon, Aminah Wali, Chatura N. Jayakody, Jacob Troutman, Andrew W. McFadden, Joshua Wooten et al. « High-throughput small molecule screen identifies inhibitors of aberrant chromatin accessibility ». Proceedings of the National Academy of Sciences 113, n^o 11 (29 février 2016) : 3018–23. http://dx.doi.org/10.1073/pnas.1521827113.

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Mutations in chromatin-modifying proteins and transcription factors are commonly associated with a wide variety of cancers. Through gain- or loss-of-function, these mutations may result in characteristic alterations of accessible chromatin, indicative of shifts in the landscape of regulatory elements genome-wide. The identification of compounds that reverse a specific chromatin signature could lead to chemical probes or potential therapies. To explore whether chromatin accessibility could serve as a platform for small molecule screening, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE), a chemical method to enrich for nucleosome-depleted genomic regions, as a high-throughput, automated assay. After demonstrating the validity and robustness of this approach, we applied this method to screen an epigenetically targeted small molecule library by evaluating regions of aberrant nucleosome depletion mediated by EWSR1-FLI1, the chimeric transcription factor critical for the bone and soft tissue tumor Ewing sarcoma. As a class, histone deacetylase inhibitors were greatly overrepresented among active compounds. These compounds resulted in diminished accessibility at targeted sites by disrupting transcription of EWSR1-FLI1. Capitalizing on precise differences in chromatin accessibility for drug discovery efforts offers significant advantages because it does not depend on the a priori selection of a single molecular target and may detect novel biologically relevant pathways.

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Maillard, Michel C., Celia Dominguez, Mark J. Gemkow, Florian Krieger, Hyunsun Park, Sabine Schaertl, Dirk Winkler et Ignacio Muñoz-Sanjuán. « A Label-Free LC/MS/MS-Based Enzymatic Activity Assay for the Detection of Genuine Caspase Inhibitors and SAR Development ». Journal of Biomolecular Screening 18, n^o 8 (24 juin 2013) : 868–78. http://dx.doi.org/10.1177/1087057113492851.

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The resurgence of interest in caspases (Csp) as therapeutic targets for the treatment of neurodegenerative diseases prompted us to examine the suitability of published nonpeptidic Csp-3 and Csp-6 inhibitors for our medicinal chemistry programs. To support this effort, fluorescence-based Csp-2, Csp-3, and Csp-6 enzymatic assays were optimized for robustness against apparent enzyme inhibition caused by redox-cycling or aggregating compounds. The data obtained under these improved conditions challenge the validity of previously published data on Csp-3 and Csp-6 inhibitors for all but one series, namely, the isatins. Furthermore, in this series, it was observed that the nature of the rhodamine-labeled substrate, typically used to measure caspase activity, interfered with the pharmacological sensitivity of the Csp-2 assay. As a result, a liquid chromatography/tandem mass spectrometry–based assay that eliminates label-dependent assay interference was developed for Csp-2 and Csp-3. In these label-free assays, the activity values of the Csp-2 and Csp-3 reference inhibitors were in agreement with those obtained with the fluorogenic substrates. However, isatin 10a was 50-fold less potent in the label-free Csp-2 assay compared with the rhodamine-based fluorescence format, thus proving the need for an orthogonal readout to validate inhibitors in this class of targets highly susceptible to artifactual inhibition.

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Perrin, Dominique, Christèle Frémaux, Dominique Besson, Wolfgang HB Sauer et Alexander Scheer. « A Microfluidics-Based Mobility Shift Assay to Discover New Tyrosine Phosphatase Inhibitors ». Journal of Biomolecular Screening 11, n^o 8 (décembre 2006) : 996–1004. http://dx.doi.org/10.1177/1087057106294094.

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Protein tyrosine phosphatases (PTPs) play key roles in regulating tyrosine phosphorylation levels in cells. Since the discovery of PTP1B as a major drug target for diabetes and obesity, PTPs have emerged as a new and promising class of signaling targets for drug development in a variety of therapeutic areas. The routine use of generic substrate 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP) in our hands led to the discovery of very similar and often not very selective molecules. Therefore, to increase the chances to discover novel chemical scaffolds, a side-by-side comparison between the DiFMUP assay and a chip-based mobility shift assay with a specific phosphopeptide was performed, on 1 PTP, using a focused set of compounds. Assay robustness and sensitivity were comparable for both the DiFMUP and mobility shift assays. The off-chip mobility shift assay required a longer development time because of identification, synthesis, and characterization of a specific peptide, and its cost per point was higher. However, although most potent scaffolds found with the DiFMUP assay were confirmed in the mobility shift format, the off-chip mobility shift assay led to the identification of previously unidentified chemical scaffolds with improved druglike properties.

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Tykvart, Jan, Václav Navrátil, Michael Kugler, Pavel Šácha, Jiří Schimer, Anna Hlaváčková, Lukáš Tenora et al. « Identification of Novel Carbonic Anhydrase IX Inhibitors Using High-Throughput Screening of Pooled Compound Libraries by DNA-Linked Inhibitor Antibody Assay (DIANA) ». SLAS DISCOVERY : Advancing the Science of Drug Discovery 25, n^o 9 (26 mai 2020) : 1026–37. http://dx.doi.org/10.1177/2472555220918836.

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The DNA-linked inhibitor antibody assay (DIANA) has been recently validated for ultrasensitive enzyme detection and for quantitative evaluation of enzyme inhibitor potency. Here we present its adaptation for high-throughput screening of human carbonic anhydrase IX (CAIX), a promising drug and diagnostic target. We tested DIANA’s performance by screening a unique compound collection of 2816 compounds consisting of lead-like small molecules synthesized at the Institute of Organic Chemistry and Biochemistry (IOCB) Prague (“IOCB library”). Additionally, to test the robustness of the assay and its potential for upscaling, we screened a pooled version of the IOCB library. The results from the pooled screening were in agreement with the initial nonpooled screen with no lost hits and no false positives, which shows DIANA’s potential to screen more than 100,000 compounds per day. All DIANA screens showed a high signal-to-noise ratio with a Z′ factor of >0.89. The DIANA screen identified 13 compounds with Ki values equal to or better than 10 µM. All retested hits were active also in an orthogonal enzymatic assay showing zero false positives. However, further biophysical validation of identified hits revealed that the inhibition activity of several hits was caused by a single highly potent CAIX inhibitor, being present as a minor impurity. This finding eventually led us to the identification of three novel CAIX inhibitors from the screen. We confirmed the validity of these compounds by elucidating their mode of binding into the CAIX active site by x-ray crystallography.

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Thorpe, James H., Emma V. Edgar, Kathrine J. Smith, Xiao Q. Lewell, Monika Rella, Gemma V. White, Oxana Polyakova et al. « Evaluation of a crystallographic surrogate for kallikrein 5 in the discovery of novel inhibitors for Netherton syndrome ». Acta Crystallographica Section F Structural Biology Communications 75, n^o 5 (26 avril 2019) : 385–91. http://dx.doi.org/10.1107/s2053230x19003169.

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The inhibition of kallikrein 5 (KLK5) has been identified as a potential strategy for treatment of the genetic skin disorder Netherton syndrome, in which loss-of-function mutations in the SPINK5 gene lead to down-regulation of the endogenous inhibitor LEKTI-1 and profound skin-barrier defects with severe allergic manifestations. To aid in the development of a medicine for this target, an X-ray crystallographic system was developed to facilitate fragment-guided chemistry and knowledge-based drug-discovery approaches. Here, the development of a surrogate crystallographic system in place of KLK5, which proved to be challenging to crystallize, is described. The biochemical robustness of the crystallographic surrogate and the suitability of the system for the study of small nonpeptidic fragments and lead-like molecules are demonstrated.

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Gill, Joan Cox, Craig M. Kessler et David L. Cooper. « The Robustness, Validity, and Potential Usefulness of Registry Data for Understanding the Treatment Practices, Safety, and Efficacy of New Therapies for Rare Bleeding Disorders : The Experience of the Hemophilia and Thrombosis Research Society (HTRS) Registry (2004–2007) ». Blood 112, n^o 11 (16 novembre 2008) : 4506. http://dx.doi.org/10.1182/blood.v112.11.4506.4506.

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Abstract In 1999, the Hemophilia Research Society established a registry to collect information on individuals diagnosed with bleeding disorders and on their bleeding episodes. Concurrently, the prospective database was intended to serve as a mechanism to satisfy the post-marketing surveillance requirements of the FDA to assess the safety and efficacy of rFVIIa (NovoSeven®, Novo Nordisk A/S) administered to individuals with congenital hemophilia complicated by alloantibody inhibitors to FVIII or FIX. On January 1, 2004, the database format was re-launched on a 2nd generation web-based platform and designated as the HTRS Registry. No data were transferred between databases. This study examines the data captured in the HTRS registry from January 2004-December 2007. The HTRS registry is a web-based single database with 11 component forms and 1564 fields. Any sites or physicians affiliated with the HTRS can participate in the registry after obtaining IRB approval and providing patients with an informed consent to capture de-identified information. Over this interval, 83 sites were IRB approved to participate, and all but 11 entered some data. Assessment of the accuracy and validity of the data contained in the registry was performed by an independent third party as part of an audit in early 2008. Overall there are 2,081 patient registration records in the HTRS database. Of these, 373 patients with ongoing treatment required merger of their data from the initial HRS Registry. A sub-cohort audit of all patients in the HTRS registry indicated that the diagnosis and inhibitor status and elements of the demographic information were accurate in 43/43 patient charts examined. The largest group of patients represent those with congenital hemophilia (Total, 1,432; A, 1,145; B, 287) and congenital hemophilia with inhibitors (Total, 354; A, 321; B, 33). Other common diagnoses were von Willebrand Disease (497), acquired hemophilia (48), congenital FVII deficiency (30), and inherited qualitative platelet disorders (29). A total of 5,144 bleeding events were captured for 473 patients, including 3,445 bleeds in congenital hemophilia, and 3,007 in 354 patients with alloantibody inhibitors. There were 2,532 bleeds in 293 patients in whom rFVIIa was administered alone or in combination with other agents. These included 2,099 bleeds in patients with congenital hemophilia, of which 1,702 were in 117 patients with inhibitors to FVIII or FIX. Recombinant FVIIa use was also reported in other patient groups, including congenital hemophilia without inhibitors (397 bleeds), congenital FVII deficiency (54), acquired hemophilia (38), Glanzmann’s thrombasthenia (23), and von Willebrand disease (9). A total of 18 serious adverse events were reported in the registry and forwarded to the manufacturer(s) regardless of relationship to therapy. In the United States (US) clinical research efforts have been focused primarily on evidence based outcomes and development of new therapeutic agents in large disease populations. For rare disorders, such as hemophilia complicated by alloantibody inhibitors, this is not practical or statistically conclusive. An alternative approach to understanding the safety and efficacy of new therapeutic agents in so-called “orphan diseases” involves the analysis of the “collective” experience of patients included in a longitudinal database. This is a labor intensive endeavor, which in the US has been subjugated to the need to deliver care to patients in a rapid fashion with limited infrastructure support. Thus, the documentation of prescribing habits, response to varying treatment modalities, and the reporting of adverse events have lagged. This is in contrast to many national health care systems outside the US, which mandate and finance such activities. The HTRS registry represents an industry- funded effort to satisfy a FDA mandate to monitor the longitudinal safety and efficacy of a clotting factor replacement product for alloantibody inhibitor patients. However, the supervision and oversight of the registry are based in an independent cooperative clinical research group, the HTRS. The significant amount of data accumulated over a 4 year period in the HTRS database will provide insight and important “signals” into current treatment practices and the safety and efficacy of treatment modalities, particularly for more severe bleeds that are treated in an HTC setting.

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Kumar, Parvin, et Ashwani Kumar. « Monte Carlo Method Based QSAR Studies of Mer Kinase Inhibitors in Compliance with OECD Principles ». Drug Research 68, n^o 04 (9 octobre 2017) : 189–95. http://dx.doi.org/10.1055/s-0043-119288.

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AbstractMonte Carlo method based QSAR studies for inhibitors of Mer kinase, a potential novel target for cancer treatment, has been carried out using balance of correlation technique. The data was divided into three random and dissimilar splits and hybrid optimal descriptors derived from SMILES and hydrogen filled graphs based notations were used for construction of QSAR models. The generated models have good fitting ability, robustness, generalizability and internal predictive ability. The external predictive ability has been tested using multiple criteria and described models exhibited good performance in all of these tests. The values of R2, Q2, R2 test, Q2 test, R2 m and ∆R2 m for the best model are 0.9502, 0.9388, 0.9469, 0.9083, 0.7534 and 0.0894 respectively. Also, the structural characteristics responsible for enhancement and reduction of activity have been extracted. Further, the agreement with the OECD rules for QSAR model has been discussed.

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Wu, Ge, Yue Yuan et C. Nicholas Hodge. « Determining Appropriate Substrate Conversion for Enzymatic Assays in High-Throughput Screening ». Journal of Biomolecular Screening 8, n^o 6 (décembre 2003) : 694–700. http://dx.doi.org/10.1177/1087057103260050.

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It is generally accepted that the conversion of substrate should be kept at less than 10% of the total substrate used when studying enzyme kinetics. However, 10% or less substrate conversion often will not produce sufficient signal changes required for robust high-throughput screening (HTS). To increase the signal-to-background ratio, HTS is often performed at higher than 10% substrate conversion. Because the consequences of high substrate conversion are poorly understood, the screening results are sometimes questioned by enzymologists. The quality of an assay is judged by the ability to detect an inhibitor under HTS conditions, which depends on the robustness of the primary detection signal (Z factor) and the sensitivity to an inhibitor. The assay sensitivity to an inhibitor is reflected in the observed IC50 value or percent inhibition at a fixed compound concentration when single-point data are collected. The major concern for an enzymatic assay under high substrate conversion is that the sensitivity of the screen may be compromised. Here we derive the relationship between the IC 50 value for a given inhibitor and the percentage of substrate conversion using a first-order kinetic model under conditions that obey Henri-Michaelis-Menten kinetics. The derived theory was further verified experimentally with a cAMP-dependent protein kinase. This model provides guidance for assay developers to choose an appropriate substrate conversion in designing an enzymatic assay, balancing the needs for robust signal and sensitivity to inhibitors.

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Janssens, Birgit, Simon Caerels et Chantal Mathieu. « SGLT inhibitors in type 1 diabetes : weighing efficacy and side effects ». Therapeutic Advances in Endocrinology and Metabolism 11 (janvier 2020) : 204201882093854. http://dx.doi.org/10.1177/2042018820938545.

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Even before sodium-glucose cotransporter inhibitors (SGLTi) became popular agents for the treatment of people with type 2 diabetes (T2DM), clinicians had explored their potential as adjunct therapies in type 1 diabetes (T1DM). Several trials have demonstrated improved glycemic control (compared with placebo) and a decrease in glucose variability with a clinically relevant increase of time in range. In addition, weight loss and decreased systolic blood pressure are observed. The magnitude of the effects observed depends on the type of SGLTi, the dose administrated, and the duration of observation in the studies. As seen in T2DM, there was an increase in the risk of urogenital mycotic infections, but no increase in the risk of severe hypoglycemia. However, concerns arose regarding an increase in incidence of diabetic ketoacidosis. Mitigation strategies, including careful patient selection, extensive education of patients and (para)medical personnel, adequate insulin dose titration, and the adoption of a ketone-centered approach, are suggested. In different areas of the world, SGLTi are approved for use in T1DM with restrictions concerning patient selection and SGLTi dose. Real-world data on the effect of introduction of SGLTi in people with T1DM will yield insight on the robustness of glycemic effects over time, and allow us to determine whether the positive risk–benefit profile observed in clinical trials can be translated to the real world.

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Dabade, Sapna Jain, Dheeraj Mandloi, Amritlal V. Bajaj et Naveen Dhingra. « GA-SMLR-Based QSAR Modeling and Molecular Docking Studies of Bisamidine Derivatives as NMT Inhibitors ». International Journal of Quantitative Structure-Property Relationships 5, n^o 4 (octobre 2020) : 1–31. http://dx.doi.org/10.4018/ijqspr.2020100101.

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The present investigation deals with a combination of genetic algorithm-stepwise multiple linear regression (GA-SMLR)-based QSAR modeling and molecular docking applied to bisamidine analogues in an attempt to explore their role as novel NMT inhibitors of Candida albicans. In this regard, 43 bisamidine analogues were investigated for the development of mathematical models. The robustness of the proposed QSAR model was not only ascertained through traditionally used internal and external validation statistical parameters (Q2= 0.740, R2 = 0.819, R_Pred^2 = 0.636) but also through various R_(m)^2 metrics proposed by Roy and Mitra. The descriptors recognized in the QSAR analysis have culminated a significant role of atomic van der Waals volume, topology, nature of bond and dipole moment to modulate the antifungal activity of compounds under investigation. The most active compound revealed enhanced binding potency with MolDock score of -183.451 kcal/mol and displayed hydrogen bond interactions with active amino acids Leu177, Thr211, Tyr225, and IIe111 of NMT.

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Ganguly, S., et V. Gopalakrishnan. « 3D QSAR Studies of DAMNI Analogs as Possible Non-nucleoside Reverse Transcriptase Inhibitors ». E-Journal of Chemistry 5, s2 (2008) : 1103–13. http://dx.doi.org/10.1155/2008/712930.

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The non-nucleoside inhibitors ofHIV-1-reverse transcriptase (NNRTIs) are an important class of drugs employed in antiviral therapy. Recently, a novel family ofNNRTIs commonly referred to as 1-[2-diarylmethoxy] ethyl) 2-methyl-5-nitroimidazoles (DAMNI) derivatives have been discovered. The 3D-QSARstudies onDAMNIderivatives asNNRTIs was performed by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods to determine the factors required for the activity of these compounds. The global minimum energy conformer of the template molecule 15, the most active molecule of the series, was obtained by simulated annealing method and used to build the structures of the molecules in the dataset. The combination of steric and electrostatic fields inCoMSIAgave the best results with cross-validated and conventional correlation coefficients of 0.654 and 0.928 respectively. The predictive ability ofCoMFAandCoMSIAwere determined using a test set of tenDAMNIderivatives giving predictive correlation coefficients of 0.92 and 0.98 respectively indicating good predictive power. Further, the robustness of the models was verified by bootstrapping analysis. The information obtained fromCoMFAandCoMSIA3Dcontour maps may be of utility in the design of more potentDAMNIanalogs asNNRTIs in future.

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Chhokar, Nisha, Sourav Kalra, Monika Chauhan, Anjana Munshi et Raj Kumar. « Quinoline-based Protein–protein Interaction Inhibitors of LEDGF/p75 and HIV Integrase : An In Silico Study ». Current Topics in Medicinal Chemistry 18, n^o 32 (5 mars 2019) : 2800–2815. http://dx.doi.org/10.2174/1568026619666190208164801.

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The failure of the Integrase Strand Transfer Inhibitors (INSTIs) due to the mutations occurring at the catalytic site of HIV integrase (IN) has led to the design of allosteric integrase inhibitors (ALLINIs). Lens epithelium derived growth factor (LEDGF/p75) is the host cellular cofactor which helps chaining IN to the chromatin. The protein-protein interactions (PPIs) were observed at the allosteric site (LEDGF/p75 binding domain) between LEDGF/p75 of the host cell and IN of virus. In recent years, many small molecules such as CX04328, CHIBA-3053 and CHI-104 have been reported as LEDGF/p75-IN interaction inhibitors (LEDGINs). LEDGINs have emerged as promising therapeutics to halt the PPIs by binding at the interface of both the proteins. In the present work, we correlated the docking scores for the reported LEDGINs containing quinoline scaffold with the in vitro biological data. The hierarchal clustering method was used to divide the compounds into test and training set. The robustness of the generated model was validated by q2 and r2 for the predicted set of compounds. The generated model between the docking score and biological data was assessed to predict the activity of the hits (quinoline scaffold) obtained from virtual screening of LEDGINs providing their structureactivity relationships to aim for the generation of potent agents.

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