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Haddison, Eposi C., Leila H. Abdullahi, Rudzani Muloiwa, Gregory D. Hussey, and Benjamin M. Kagina. "Comparison of school based and supplemental vaccination strategies in the delivery of vaccines to 5-19 year olds in Africa - a systematic review." F1000Research 6 (October 13, 2017): 1833. http://dx.doi.org/10.12688/f1000research.12804.1.
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Background: Some vaccine preventable diseases (VPDs) still remain a public health burden in many African countries. The occurrence of VPDs in all age groups has led to the realization of the need to extend routine immunisation services to school age children, adolescents and adults. Supplemental immunisation activities (SIAs) and school based vaccinations (SBVs) are common strategies used to complement the expanded programme on immunisation (EPI). This review aimed to assess the effectiveness of SIAs compared to SBVs in the administration of vaccines to 5-19 year olds in Africa. Methods: Systematic review methods were used to address our study aim. Several electronic databases were searched up to March 30, 2017 for primary studies investigating the delivery of vaccines via SIAs or SBVs to 5-19 year olds. This search was complemented by browsing reference lists of potential studies obtained from search outputs. Outcomes considered for inclusion were: vaccination coverage, costs of the strategy or its effect on routine immunisation services. Results: Out of the 4938 studies identified, 31 studies met the review inclusion criteria. Both SIAs and SBVs showed high vaccination coverage. However, the SIAs reported higher coverage than SBVs: 91% (95% CI: 84%, 98%) versus 75% (95% CI: 67%, 83%). In most settings, SBVs were reported to be more expensive than SIAs. The SIAs were found to negatively affect routine immunisation services. Conclusions: Both SIAs and SBVs are routinely used to complement the EPI in the delivery of vaccines in Africa. In settings where school enrolment is suboptimal, as is the case in many African countries, our results show SIAs may be more effective in reaching school age children and adolescents than SBVs. Our results re-iterate the importance of evaluating systematic evidence to best inform African authorities on the optimal vaccine delivery strategies targeting school age children and adolescents.
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Istyastono, Enade Perdana. "Binary Quantitative Structure-Activity Relationship Analysis to Increase the Predictive Ability of Structure-Based Virtual Screening Campaigns Targeting Cyclooxygenase-2." Indonesian Journal of Chemistry 17, no. 2 (July 31, 2017): 322. http://dx.doi.org/10.22146/ijc.24172.
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Structure-Based Virtual Screening (SBVS) campaigns employing Protein-Ligand Interaction Fingerprints (PLIF) identification have served as a powerful strategy in fragments and ligands identification, both retro- and prospectively. Most of the SBVS campaigns employed PLIF by comparing them to a reference PLIF to calculate the Tanimoto-coefficient. Since the approach was reference dependent, it could lead to a very different discovery path if a different reference was used. In this article, references independent approach, i.e. decision trees construction using docking score and PLIF as the descriptors to increase the predictive ability of the SBVS campaigns in the identification of ligands for cyclooxygenase-2 is presented. The results showed that the binary Quantitative-Structure Activity Relationship (QSAR) analysis could significantly increase the predictive ability of the SBVS campaign. Moreover, the selected decision tree could also pinpoint the molecular determinants of the ligands binding to cyclooxygenase-2.
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Istyastono, Enade P., Florentinus Dika Octa Riswanto, Nunung Yuniarti, Vivitri D. Prasasty, and Sudi Mungkasi. "PyPLIF HIPPOS and Receptor Ensemble Docking Increase the Prediction Accuracy of the Structure-Based Virtual Screening Protocol Targeting Acetylcholinesterase." Molecules 27, no. 17 (September 2, 2022): 5661. http://dx.doi.org/10.3390/molecules27175661.
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In this article, the upgrading process of the structure-based virtual screening (SBVS) protocol targeting acetylcholinesterase (AChE) previously published in 2017 is presented. The upgraded version of PyPLIF called PyPLIF HIPPOS and the receptor ensemble docking (RED) method using AutoDock Vina were employed to calculate the ensemble protein–ligand interaction fingerprints (ensPLIF) in a retrospective SBVS campaign targeting AChE. A machine learning technique called recursive partitioning and regression trees (RPART) was then used to optimize the prediction accuracy of the protocol by using the ensPLIF values as the descriptors. The best protocol resulting from this research outperformed the previously published SBVS protocol targeting AChE.
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Lucumi, Armando, Sara Robledo, Vivian Gama, and Nancy G. Saravia. "Sensitivity of Leishmania viannia panamensis to Pentavalent Antimony Is Correlated with the Formation of Cleavable DNA-Protein Complexes." Antimicrobial Agents and Chemotherapy 42, no. 8 (August 1, 1998): 1990–95. http://dx.doi.org/10.1128/aac.42.8.1990.
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ABSTRACT The emergence of Leishmania less sensitive to pentavalent antimonial agents (SbVs), the report of inhibition of purified topoisomerase I of Leishmania donovani by sodium stibogluconate (Pentostam), and the uncertain mechanism of action of antimonial drugs prompted an evaluation of SbVs in the stabilization of cleavable complexes in promastigotes of Leishmania(Viannia). The effect of camptothecin, an inhibitor of topoisomerase, and additive-free meglumine antimoniate (Glucantime) on the stabilization of cleavable DNA-protein complexes associated with the inhibition of topoisomerase was assessed in the human promonocytic cell line U-937, promastigotes of L. (Viannia)panamensis selected for SbV resistance in vitro, and the corresponding wild-type strain. The stabilization of cleavable complexes and the 50% effective dose (ED50) of SbVs for parasites isolated from patients with relapses were also evaluated. The median ED50 for the wild-type strain was 16.7 μg of SbV/ml, while that of the line selected for resistance was 209.5 μg of SbV/ml. Treatment with both meglumine antimoniate and sodium stibogluconate (20 to 200 μg of SbV/ml) stabilized DNA-protein complexes in the wild-type strain but not the resistant line. The ED50s of the SbVs for Leishmania strains from patients with relapses was comparable to those for the line selected for in vitro resistance, and DNA-protein complexes were not stabilized by exposure to meglumine antimoniate. Cleavable complexes were observed in all Leishmania strains treated with camptothecin. Camptothecin stabilized cleavable complexes in U-937 cells; SbVs did not. The selective effect of the SbVs on the stabilization of DNA-protein complexes in Leishmania and the loss of this effect in naturally resistant or experimentally derived SbV-resistantLeishmania suggest that topoisomerase may be a target of antimonial drugs.
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Istyastono, Enade Perdana, Nunung Yuniarti, Maywan Hariono, Sri Hartati Yuliani, and Florentinus Dika Octa Riswanto. "BINARY QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS IN RETROSPECTIVE STRUCTURE-BASED VIRTUAL SCREENING CAMPAIGNS TARGETING ESTROGEN RECEPTOR ALPHA." Asian Journal of Pharmaceutical and Clinical Research 10, no. 12 (December 1, 2017): 206. http://dx.doi.org/10.22159/ajpcr.2017.v10i12.20667.
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Objective: The objective of this study is to construct predictive unbiased structure-based virtual screening (SBVS) protocols to identify potent ligands for estrogen receptor alpha by combining molecular docking, protein-ligand interaction fingerprinting (PLIF), and binary quantitative structure-activity relationship (QSAR) analysis using recursive partition and regression tree method.Methods: Employing the enhanced version of a directory of useful decoys, SBVS protocols using molecular docking simulations, and PLIF were constructed and retrospectively validated. To avoid bias, SMILES format of the compounds was used. The predictive abilities of the SBVS protocols were then compared based on the enrichment factor (EF) and the F-measure values.Results: The SBVS protocols resulted in this research were SBVS_1 (employing docking scores of the best pose on every compound to rank the results and selecting compounds within 1% false positives as positive), SBVS_2 (employing decision tree resulted from the binary QSAR analysis using docking scores and PLIF bitstrings of the best pose of every compound as descriptors), and SBVS_3 (employing decision tree resulted from the binary QSAR analysis using ensemble PLIF of the selected poses from optimized docking score as the cutoff). The EF values of SBVS_1, SBVS_2, and SBVS_3 are 28.315, 576.084, and 713.472, respectively, while their F-measure values are 0.310, 0.573, and 0.769, respectively.Conclusion: Highly predictive unbiased SBVS protocols to identify potent estrogen receptor alpha ligands were constructed. Further application in prospective screening is therefore highly suggested.
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Lee, Yuno, Sae-Bom Yoon, Hyowon Hong, Hyun Young Kim, Daeyoung Jung, Byoung-San Moon, Woo-Kyu Park, et al. "Discovery of GSK3β Inhibitors through In Silico Prediction-and-Experiment Cycling Strategy, and Biological Evaluation." Molecules 27, no. 12 (June 14, 2022): 3825. http://dx.doi.org/10.3390/molecules27123825.
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Direct inhibitors of glycogen synthase kinase 3β (GSK3β) have been investigated and reported for the past 20 years. In the search for novel scaffold inhibitors, 3000 compounds were selected through structure-based virtual screening (SBVS), and then high-throughput enzyme screening was performed. Among the active hit compounds, pyrazolo [1,5-a]pyrimidin-7-amine derivatives showed strong inhibitory potencies on the GSK3β enzyme and markedly activated Wnt signaling. The result of the molecular dynamics (MD) simulation, enhanced by the upper-wall restraint, was used as an advanced structural query for the SBVS. In this study, strong inhibitors designed to inhibit the GSK3β enzyme were discovered through SBVS. Our study provides structural insights into the binding mode of the inhibitors for further lead optimization.
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Yuniarti, Nunung, Sudi Mungkasi, Sri Hartati Yuliani, and Enade Perdana Istyastono. "Development of a Graphical User Interface Application to Identify Marginal and Potent Ligands for Estrogen Receptor Alpha." Indonesian Journal of Chemistry 19, no. 2 (April 9, 2019): 531. http://dx.doi.org/10.22146/ijc.34561.
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Employing ensemble Protein-Ligand Interaction Fingerprints (ensPLIF) as descriptors in post retrospective Structure-Based Virtual Screening (SBVS) campaigns Quantitative Structure-Activity Relationship (QSAR) analysis has been proven to significantly increase the predictive ability in the identification of potent ligands for estrogen receptor alpha (ERα). In the research presented in this article, similar approaches have been performed to construct and retrospectively validate an SBVS protocol to identify marginal ligands for ERα. Based on both validated SBVS protocols, a graphical-user-interface (GUI) application to identify if a compound is a non-, moderate or potent ligand for ERα was developed. The GUI application was subsequently used to virtually screen genistin, genistein, daidzin, and daidzein, followed by in vitro test employing a cytotoxic assay using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) method.
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Istyastono, Enade Perdana. "CONSTRUCTION AND OPTIMIZATION OF STRUCTURE-BASED VIRTUAL SCREENING PROTOCOLS TO IDENTIFY CYCLOOXYGENASE-1 INHIBITORS USING OPEN BABEL, SPORES AND PLANTS." Indonesian Journal of Chemistry 12, no. 2 (June 4, 2012): 141–45. http://dx.doi.org/10.22146/ijc.21354.
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Structure-Based Virtual Screening (SBVS) protocols to identify cyclooxygenase-1 (COX-1) inhibitors have been constructed and optimized based on their Root Mean Square Deviation (RMSD) values of the docked pose and the crystal structure pose of the reference ligand. Employing a COX-1 structure obtained from the Protein Data Bank (pdb) with code 2OYE as the reference protein and PLANTS1.2 as the molecular docking simulation program, the SBVS protocols were mainly built. The preparation steps involved SPORES and Open Babel, while the results analysis involved PyMOL to calculate the RMSD and R computational statistics software to perform the statistics calculations. The results show that these construction and optimization processes could provide an SBVS protocol to identify COX-1 inhibitors that is accurately able to redock the reference ligand with the RMSD value of 0.633 Å.
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Zhu, Hui, Yulin Zhang, Wei Li, and Niu Huang. "A Comprehensive Survey of Prospective Structure-Based Virtual Screening for Early Drug Discovery in the Past Fifteen Years." International Journal of Molecular Sciences 23, no. 24 (December 15, 2022): 15961. http://dx.doi.org/10.3390/ijms232415961.
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Structure-based virtual screening (SBVS), also known as molecular docking, has been increasingly applied to discover small-molecule ligands based on the protein structures in the early stage of drug discovery. In this review, we comprehensively surveyed the prospective applications of molecular docking judged by solid experimental validations in the literature over the past fifteen years. Herein, we systematically analyzed the novelty of the targets and the docking hits, practical protocols of docking screening, and the following experimental validations. Among the 419 case studies we reviewed, most virtual screenings were carried out on widely studied targets, and only 22% were on less-explored new targets. Regarding docking software, GLIDE is the most popular one used in molecular docking, while the DOCK 3 series showed a strong capacity for large-scale virtual screening. Besides, the majority of identified hits are promising in structural novelty and one-quarter of the hits showed better potency than 1 μM, indicating that the primary advantage of SBVS is to discover new chemotypes rather than highly potent compounds. Furthermore, in most studies, only in vitro bioassays were carried out to validate the docking hits, which might limit the further characterization and development of the identified active compounds. Finally, several successful stories of SBVS with extensive experimental validations have been highlighted, which provide unique insights into future SBVS drug discovery campaigns.
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Chang, Ju-Chun, Zih-Ting Chang, Chong-Yu Ko, Yue-Wen Chen, and Yu-Shin Nai. "Genomic Sequencing and Comparison of Sacbrood Viruses from Apis cerana and Apis mellifera in Taiwan." Pathogens 10, no. 1 (December 28, 2020): 14. http://dx.doi.org/10.3390/pathogens10010014.
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Sacbrood virus (SBV) was the first identified bee virus and shown to cause serious epizootic infections in the population of Apis cerana in Taiwan in 2015. Herein, the whole genome sequences of SBVs in A. cerana and A. mellifera were decoded and designated AcSBV-TW and AmSBV-TW, respectively. The whole genomes of AcSBV-TW and AmSBV-TW were 8776 and 8885 bp, respectively, and shared 90% identity. Each viral genome encoded a polyprotein, which consisted of 2841 aa in AcSBV-TW and 2859 aa in AmSBV-TW, and these sequences shared 95% identity. Compared to 54 other SBVs, the structural protein and protease regions showed high variation, while the helicase was the most highly conserved region among SBVs. Moreover, a 17-amino-acid deletion was found in viral protein 1 (VP1) region of AcSBV-TW compared to AmSBV-TW. The phylogenetic analysis based on the polyprotein sequences and partial VP1 region indicated that AcSBV-TW was grouped into the SBV clade with the AC-genotype (17-aa deletion) and was closely related to AmSBV-SDLY and CSBV-FZ, while AmSBV-TW was grouped into the AM-genotype clade but branched independently from other AmSBVs, indicating that the divergent genomic characteristics of AmSBV-TW might be a consequence of geographic distance driving evolution, and AcSBV-TW was closely related to CSBV-FZ, which originated from China. This 17-amino-acid deletion could be found in either AcSBV or AmSBV in Taiwan, indicating cross-infection between the two viruses. Our data revealed geographic and host specificities between SBVs. The amino acid difference in the VP1 region might serve as a molecular marker for describing SBV cross-infection.
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Mustapha, M. T., D. R. Flower, and A. K. Chattopadhyay. "Virtual Screening of Kinase Based Drugs: Statistical Learning Towards Drug Repositioning." Journal of Nanotechnology in Diagnosis and Treatment 8 (December 12, 2022): 23–34. http://dx.doi.org/10.12974/2311-8792.2022.08.03.
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Kinases are phosphate catalysing enzymes that have traditionally proved difficult to target against ligands,and hence inefficacious in drug development. There are two colluding reasons for this. First is the issue of specificity. The homogeneity that exists between the kinase ATP-binding pockets makes it a non-realisable target to developcompounds that would inhibit only one out of 538 protein kinases encoded by the human genome, without inhibitingsome of the others. Second, producing compounds with the required efficacy to rival the millimolar ATP concentrations present in cells is stoichiometrically inefficient. This study uses a recently propounded computational strategy based onStructure Based Virtual Screening (SBVS) that was previously benchmarked on 999 DUD-E protein decoys(Chattopadhyay et al, Int Sc. Comp. Life Sciences 2022), to rank potential ligands, or by extension rank kinase-ligand pairs, identifying best matching ligand:kinase docking pairs. The results of the SBVS campaign employing severalcomputational algorithms reveal variations in the preferred top hits. To address this, we introduce a novel consensusscoring algorithm by sampling statistics across four independent statistical universality classes, statistically combining docking scores from ten docking programs (DOCK, Quick Vina-W, Vina Carb, PLANTS, Autodock, QuickVina2,QuickVina21, Smina, Autodock Vina and VinaXB) to create a holistic SBVS formulation that can identify active ligandsfor any target. Our results demonstrate that CS provides improved ligand:kinase docking fidelity when compared to individual docking platforms, requiring only a small number of docking combinations, and can serve as a viable andthrifty alternative to expensive docking platforms.
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Setiawati, Agustina, Florentinus Dika Octa Riswanto, Sri Hartati Yuliani, and Enade Perdana Istyastono. "Retrospective Validation of a Structure-Based Virtual Screening Protocol to Identify Ligands for Estrogen Receptor Alpha and Its Application to Identify the Alpha-Mangostin Binding Pose." Indonesian Journal of Chemistry 14, no. 2 (July 25, 2014): 103–8. http://dx.doi.org/10.22146/ijc.21245.
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The publicly available enhanced data of ligands and decoys for estrogen receptor alpha (ERα) which were recently published has made the retrospective validation of a structure-based virtual screening (SBVS) protocol to identify ligands for ERα possible. In this article, we present the retrospective validation of an SBVS protocol using PLANTS molecular docking software version 1.2 (PLANTS1.2) as the backbone software. The protocol shows better enrichment factor at 1% false positives (EF1%) value and the Area Under Curve (AUC) value of the Receiver Operator Characteristic (ROC) compared to the original published protocol. Moreover, in all 1000 iterative attempts the protocol could reproduce the co-crystal pose of 4-hydroxitamoxifen in ERα binding pocket. It shows that the protocol is not only able to identify potent ligands for ERα but also able to be employed in examining binding pose of known ligand. Thence, the protocol was successfully employed to examine the binding poses of α-mangostin, an ERα ligand found in the Garcinia mangostana, L. pericarp.
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Ferreira, Leonardo L. G., Rafaela S. Ferreira, David L. Palomino, and Adriano D. Andricopulo. "Structure-Based Virtual Screening and Biochemical Evaluation for the Identification of Novel Trypanosoma brucei Aldolase Inhibitors." Current Topics in Medicinal Chemistry 18, no. 5 (June 11, 2018): 397–405. http://dx.doi.org/10.2174/1568026618666180427150428.
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Introduction: The glycolytic enzyme fructose-1,6-bisphosphate aldolase is a validated molecular target in human African trypanosomiasis (HAT) drug discovery, a neglected tropical disease (NTD) caused by the protozoan Trypanosoma brucei. Herein, a structure-based virtual screening (SBVS) approach to the identification of novel T. brucei aldolase inhibitors is described. Distinct molecular docking algorithms were used to screen more than 500,000 compounds against the X-ray structure of the enzyme. This SBVS strategy led to the selection of a series of molecules which were evaluated for their activity on recombinant T. brucei aldolase. The effort led to the discovery of structurally new ligands able to inhibit the catalytic activity of the enzyme. Results: The predicted binding conformations were additionally investigated in molecular dynamics simulations, which provided useful insights into the enzyme-inhibitor intermolecular interactions. Conclusion: The molecular modeling results along with the enzyme inhibition data generated practical knowledge to be explored in further structure-based drug design efforts in HAT drug discovery.
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Budashko, Vitalii, Albert Sandler, and Sergii Khniunin. "Improving the method of linear-quadratic control over a physical model of vessel with azimuthal thrusters." Eastern-European Journal of Enterprise Technologies 1, no. 2 (121) (February 28, 2023): 49–71. http://dx.doi.org/10.15587/1729-4061.2023.273934.
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The object of this research is the algorithms for controlling large-scale models of sea-based vehicles (SBVs). The subject of the research is a linear-quadratic method for controlling a model of the propulsion complex with azimuthal thrusters (ATs) in the aft part. The problem is the solution between the interdependent throws of surge, sway, and yaw speeds predicted by the linear controller. Input signals are the rotational speeds and the angles of ATs propeller thrusts with respect to the diametrical plane of SBVs. During the simulation, step responses of a closed system for overload and rotation speed are compared. Simulation of speed jumps showed an adequate response, in contrast to the speed of rotation of ATs, which showed a greater impact on the system than the orientation of ATs. When modeling the rate of yaw, the behavior of the ATs angle did not correspond to its limitations inherent in the device rotating at the appropriate speed. It is concluded that this is the result of linearization of the actuators, and the proposed solution is to implement the strengthening of the task to better adapt to the rotating behavior of ATs. Despite these problems, the simulation showed the potential of the model and controller for use in similar situations. Several modifications are also offered to significantly improve the model and simulations. One of the main changes that could be made is the implementation of a predictive gain during the linearization of the ATs control system. The practical significance of the results obtained is the fact that the quadratic optimization model is an effective and reliable technique in the process of designing SBVs of various configurations of steering devices for optimal control
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Nugraha, Gerry, and Enade Perdana Istyastono. "Pembuatan Protokol Penapisan Virtual Berbasis Stuktur (pvbs) untuk Identifikasi Ligan Inhibitor Reseptor Platelet-Activating Factor (PAF-r) sebagai Target Terapeutik Asma menggunakan YASARA." Jurnal Riset Kimia 11, no. 1 (March 30, 2020): 35–42. http://dx.doi.org/10.25077/jrk.v11i1.346.
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Platelet-activating factor receptors (PAF-r) is known as one of the receptors that affect asthma, while the Y-21480 ligand is reported as an effective, specific, and active PAF-r antagonist for asthma patients. Research in building structure-based virtual screening protocol (SBVS) for identification of PAF-r ligand inhibitors has been performed, the receptor crystal structure was obtained from the Protein Data Bank (PDB ID: 5zkp), while the ligand used as a leading compound is Y-24180, obtained from U.S. National Library of Medicine. Interactions between ligands and receptors are observed through molecular dynamics simulations using the YASARA program at intervals up to 20 nanoseconds, ligand-receptor binding stability occurs after a time interval of 2 nanoseconds, the lowest ligand-receptor binding energy occurs at a time interval of 1,401 picoseconds. Internal validation by re-docking 1,000 times the ligand to receptor resulted in a value of Root Mean Square Deviation (RMSD) of 0.6037 Å, confirmed that SBVS protocol was accurately able to reproduce the Y-24180 ligand pose on the 5zkp crystal structure, the protocol can be used as a new approach for investigation or design of compounds that have therapeutic potential as anti-asthma.
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Nazarshodeh, Elmira, Sayed-Amir Marashi, and Sajjad Gharaghani. "Structural systems pharmacology: A framework for integrating metabolic network and structure-based virtual screening for drug discovery against bacteria." PLOS ONE 16, no. 12 (December 14, 2021): e0261267. http://dx.doi.org/10.1371/journal.pone.0261267.
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Advances in genome-scale metabolic models (GEMs) and computational drug discovery have caused the identification of drug targets at the system-level and inhibitors to combat bacterial infection and drug resistance. Here we report a structural systems pharmacology framework that integrates the GEM and structure-based virtual screening (SBVS) method to identify drugs effective for Escherichia coli infection. The most complete genome-scale metabolic reconstruction integrated with protein structures (GEM-PRO) of E. coli, iML1515_GP, and FDA-approved drugs have been used. FBA was performed to predict drug targets in silico. The 195 essential genes were predicted in the rich medium. The subsystems in which a significant number of these genes are involved are cofactor, lipopolysaccharide (LPS) biosynthesis that are necessary for cell growth. Therefore, some proteins encoded by these genes are responsible for the biosynthesis and transport of LPS which is the first line of defense against threats. So, these proteins can be potential drug targets. The enzymes with experimental structure and cognate ligands were selected as final drug targets for performing the SBVS method. Finally, we have suggested those drugs that have good interaction with the selected proteins as drug repositioning cases. Also, the suggested molecules could be promising lead compounds. This framework may be helpful to fill the gap between genomics and drug discovery. Results show this framework suggests novel antibacterials that can be subjected to experimental testing soon and it can be suitable for other pathogens.
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PHAM, Quan Minh, and Long Quoc PHAM. "VIRTUAL SCREENING STATEGIES IN DRUG DISCOVERY – A BRIEF OVERVIEW." Vietnam Journal of Science and Technology 59, no. 4 (August 13, 2021): 415. http://dx.doi.org/10.15625/2525-2518/59/4/16003.
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Computer-aided drug design has now become a compulsory tool in the drug discovery and development process which uses computational approaches to discover potential compounds with expected biological activities. Firstly, this review provides a comprehensive introduction of the virtual screening technique, knowledge and advances in both SBVS and LBVS strategies also presented. Secondly, recent database of compounds provided worldwide and drug-like parameters which are helpful in supporting the VS process will be discussed. These information will provides a good platform to estimate the advance of applying these techniques in the new drug-lead identification and optimization.
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Li, Ming, Dongliang Fei, Li Sun, and Mingxiao Ma. "Genetic and phylogenetic analysis of Chinese sacbrood virus isolates from Apis mellifera." PeerJ 7 (November 14, 2019): e8003. http://dx.doi.org/10.7717/peerj.8003.
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Background Sacbrood virus (SBV) is one of the most pathogenic honeybee viruses that exhibits host specificity and regional variations. The SBV strains that infect the Chinese honeybee Apis cerana are called Chinese SBVs (CSBVs). Methods In this study, a CSBV strain named AmCSBV-SDLY-2016 (GenBank accession No. MG733283) infecting A. mellifera was identified by electron microscopy, its protein composition was analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis and agar gel immunodiffusion assay, and its nucleotide sequence was identified using a series of reverse-transcription polymerase chain reaction fragments of AmCSBV-SDLY-2016 generated using SBV/CSBV-specific primers. To investigate phylogenetic relationships of the CSBV isolates, a phylogenetic tree of the complete open reading frames (ORF) of the CSBV sequences was constructed using MEGA 6.0; then, the similarity and recombination events among the isolated CSBV strains were analyzed using SimPlot and RDP4 software, respectively. Results Sequencing results revealed the complete 8,794-nucleotide long complete genomic RNA of the strain, with a single large ORF (189–8,717) encoding 2,843 amino acids. Comparison of the deduced amino acid sequence with the SBV/CSBV reference sequences deposited in the GenBank database identified helicase, protease, and RNA-dependent RNA polymerase domains; the structural genes were located at the 5′ end, whereas the non-structural genes were found at the 3′ end. Multiple sequence alignment showed that AmCSBV-SDLY-2016 had a 17-amino acid (aa) and a single aa deletion at positions 711–729 and 2,128, respectively, as compared with CSBV-GD-2002, and a 16-aa deletion (positions 711–713 and 715–728) as compared with AmSBV-UK-2000. However, AmCSBV-SDLY-2016 was similar to the CSBV-JLCBS-2014 strain, which infects A. cerana. AmCSBV-SDLY-2016 ORF shared 92.4–97.1% identity with the genomes of other CSBV strains (94.5–97.7% identity for deduced amino acids). AmCSBV-SDLY-2016 was least similar (89.5–90.4% identity) to other SBVs but showed maximum similarity with the previously reported CSBV-FZ-2014 strain. The phylogenetic tree constructed from AmCSBV-SDLY-2016 and 43 previously reported SBV/CSBV sequences indicated that SBV/CSBV strains clustered according to the host species and country of origin; AmCSBV-SDLY-2016 clustered with other previously reported Chinese and Asian strains (AC genotype SBV, as these strains originated from A. cerana) but was separate from the SBV genomes originating from Europe (AM genotype SBV, originating from A. mellifera). A SimPlot graph of SBV genomes confirmed the high variability, especially between the AC genotype SBV and AM genotype SBV. This genomic diversity may reflect the adaptation of SBV to specific hosts, ability of CSBV to cross the species barrier, and the spatial distances that separate CSBVs from other SBVs.
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Ghufran, Mehreen, Mehran Ullah, Haider Ali Khan, Sabreen Ghufran, Muhammad Ayaz, Muhammad Siddiq, Syed Qamar Abbas, Syed Shams ul Hassan, and Simona Bungau. "In-Silico Lead Druggable Compounds Identification against SARS COVID-19 Main Protease Target from In-House, Chembridge and Zinc Databases by Structure-Based Virtual Screening, Molecular Docking and Molecular Dynamics Simulations." Bioengineering 10, no. 1 (January 11, 2023): 100. http://dx.doi.org/10.3390/bioengineering10010100.
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Pharmacological strategies to lower the viral load among patients suffering from severe diseases were researched in great detail during the SARS-CoV-2 outbreak. The viral protease Mpro (3CLpro) is necessary for viral replication and is among the main therapeutic targets proposed, thus far. To stop the pandemic from spreading, researchers are working to find more effective Mpro inhibitors against SARS-CoV-2. The 33.8 kDa Mpro protease of SARS-CoV-2, being a nonhuman homologue, has the possibility of being utilized as a therapeutic target against coronaviruses. To develop drug-like compounds capable of preventing the replication of SARS-main CoV-2’s protease (Mpro), a computer-aided drug design (CADD) approach is extremely viable. Using MOE, structure-based virtual screening (SBVS) of in-house and commercial databases was carried out using SARS-CoV-2 proteins. The most promising hits obtained during virtual screening (VS) were put through molecular docking with the help of MOE. The virtual screening yielded 3/5 hits (in-house database) and 56/66 hits (commercial databases). Finally, 3/5 hits (in-house database), 3/5 hits (ZINC database), and 2/7 hits (ChemBridge database) were chosen as potent lead compounds using various scaffolds due to their considerable binding affinity with Mpro protein. The outcomes of SBVS were then validated using an analysis based on molecular dynamics simulation (MDS). The complexes’ stability was tested using MDS and post-MDS. The most promising candidates were found to exhibit a high capacity for fitting into the protein-binding pocket and interacting with the catalytic dyad. At least one of the scaffolds selected will possibly prove useful for future research. However, further scientific confirmation in the form of preclinical and clinical research is required before implementation.
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Kounkel, Marina, Kevin R. Covey, Keivan G. Stassun, Adrian M. Price-Whelan, Jon Holtzman, Drew Chojnowski, Penélope Longa-Peña, et al. "Double-lined Spectroscopic Binaries in the APOGEE DR16 and DR17 Data." Astronomical Journal 162, no. 5 (October 8, 2021): 184. http://dx.doi.org/10.3847/1538-3881/ac1798.
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Abstract APOGEE spectra offer ≲1 km s−1 precision in the measurement of stellar radial velocities. This holds even when multiple stars are captured in the same spectrum, as happens most commonly with double-lined spectroscopic binaries (SB2s), although random line-of-sight alignments of unrelated stars can also occur. We develop a code that autonomously identifies SB2s and higher order multiples in the APOGEE spectra, resulting in 7273 candidate SB2s, 813 SB3s, and 19 SB4s. We estimate the mass ratios of binaries, and for a subset of these systems with a sufficient number of measurements we perform a complete orbital fit, confirming that most systems with periods of <10 days have circularized. Overall, we find an SB2 fraction (F SB2) ∼ 3% among main-sequence dwarfs, and that there is not a significant trend in F SB2 with temperature of a star. We are also able to recover a higher F SB2 in sources with lower metallicity, however there are some observational biases. We also examine light curves from TESS to determine which of these spectroscopic binaries are also eclipsing. Such systems, particularly those that are also pre- and post-main sequence, are good candidates for a follow-up analysis to determine their masses and temperatures.
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Cohen, G. S., and F. Motallebi. "Sub boundary-layer vortex generators for the control of shock induced separation." Aeronautical Journal 110, no. 1106 (April 2006): 215–26. http://dx.doi.org/10.1017/s0001924000001196.
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Abstract The results of an investigation into the effects that sub-boundary layer vortex generators (SBVGs) have on reducing normal shock-induced turbulent boundary-layer separation are presented. The freestream Mach number and Reynolds number were M = 1·45 and 15·9 × 106/m, respectively. Total pressure profiles, static pressure distributions, surface total pressure distributions, oil flow visualisation and Schlieren photographs were used in the results analysis. The effects of SBVG height, lateral spacing and location upstream of the shock were investigated. A novel curved shape SBVG was also evaluated and comparisons against the conventional flat vane type were made. The results show that in all but two cases, separation was completely eliminated. As expected, the largest SBVGs with height, h = 55%δ, provided the greatest pressure recovery and maximum mixing. However, the shock pressure rise was highest for this case. The experiments showed that the mid height SBVG array with the largest spacing provided similar results to the SBVG array with the largest height. Reducing the distance to shock to 10δ upstream also showed some improvement over the SBVG position of 18δ upstream. It was suggested that total elimination of the separated region may not be required to achieve a balance of improved static pressure recovery whilst minimising the pressure rise through the shock. The effect of curving the SBVGs provided an improved near wall mixing with an improved static and surface total pressure recovery downstream of the separation line. The optimum SBVG for the current flow conditions was found to be the curved vanes of h = 40%δ, with the largest spacing, located at 18δ upstream of the shock. Overall, it was apparent from the results that in comparison to larger vortex generators with a height comparable to δ, for SBVGs the parameters involved become more important in order to obtain the highest degree of mixing from a given SBVG configuration.
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El Aissouq, Abdellah, Oussama Chedadi, Mohammed Bouachrine, and Abdelkrim Ouammou. "Identification of Novel SARS-CoV-2 Inhibitors: A Structure-Based Virtual Screening Approach." Journal of Chemistry 2021 (February 8, 2021): 1–7. http://dx.doi.org/10.1155/2021/1901484.
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The recent outbreak of the coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) in the last few months raised global health concern. Previous research described that remdesivir and ritonavir can be used as effective drugs against COVID-19. In this study, we applied the structure-based virtual screening (SBVS) on the high similar remdesivir- and ritonavir-approved drugs, selected from the DrugBank database as well as on a series of ritonavir derivatives, selected from the literature. The aim was to provide new potent SARS-CoV-2 main protease (Mpro) inhibitors with high stability. The analysis was performed using AutoDock VINA implicated in the PyRx 0.8 tool. Based on the ligand binding energy, 20 compounds were selected and then analyzed by AutoDock tools. Among the 20 compounds, 3 compounds were selected as high-potent anti-COVID-19.
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Marvaniya, Vanita, Hirak V. Joshi, Ujashkumar A. Shah, and Jayvadan K. Patel. "Docking, Synthesis and Anticancer Activity of 4-(4-(3-(4-Chloro-3-(trifluoromethyl)- phenyl)ureido)phenoxy)-N-(2-morpholinoethyl)picolinamide Derivatives." Asian Journal of Chemistry 34, no. 6 (2022): 1457–64. http://dx.doi.org/10.14233/ajchem.2022.23772.
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A new series of diaryl urea derivatives bearing pyridine moiety were designed, synthesized and evaluated for their biological activity. In this study, we applied the structure-based virtual screening (SBVS) on the high similar sorafenib approved drug, selected from the DrugBank database as well as on a series of derivatives, selected from the literature. Aim was to provide new potent anticancer agents. Analysis was performed using AutoDock VINA tools. Based on the ligand binding energy. Compounds will be synthesized by chlorination of pyridine acid derivative which further coupled with amine and form amide, amide further reaction with aminophenolic moiety and form ether which is react with other aromatic amine using CDI to produce final compound and these compounds characterized by IR, NMR and mass spectroscopic techniques. The synthesized derivatives have been evaluated to their anticancer activity in vitro by MTT assay using MCF-7 cell line. The anticancer activity indicates that compounds C1, C3, C6 and C9 have better anticancer activity.
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Cohen, G. S., and F. Motallebi. "Influence of the height of the vortex generators in the control of shock-induced separation of the boundary layers." Aeronautical Journal 112, no. 1133 (July 2008): 415–20. http://dx.doi.org/10.1017/s0001924000002372.
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Abstract Experiments have been conducted to assess the effects that sub-boundary-layer vortex generators (SBVGs) have on reducing normal shock-induced turbulent boundary-layer separation. The freestream Mach number and Reynolds number were M = 1·45 and 15·9 × 106/m, respectively. Detailed measurements of a fully developed, flat plate turbulent boundary layer were used in order to assess the performance of ten different SBVG configurations. The SBVG performance was assessed by comparing total pressure profiles measured upstream of separation and downstream of reattachment. Static pressure distributions, near surface total pressure distributions, oil flow visualisation and Schlieren photographs were also used. The effect of SBVG height was investigated. The results show the largest SBVGs with height, h = 55%δ, provided the greatest static pressure recovery and maximum mixing. However, the shock pressure rise (wave drag) was highest for this case.
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Araujo, Sheila C., Vinicius G. Maltarollo, Michell O. Almeida, Leonardo L. G. Ferreira, Adriano D. Andricopulo, and Kathia M. Honorio. "Structure-Based Virtual Screening, Molecular Dynamics and Binding Free Energy Calculations of Hit Candidates as ALK-5 Inhibitors." Molecules 25, no. 2 (January 9, 2020): 264. http://dx.doi.org/10.3390/molecules25020264.
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Activin-like kinase 5 (ALK-5) is involved in the physiopathology of several conditions, such as pancreatic carcinoma, cervical cancer and liver hepatoma. Cellular events that are landmarks of tumorigenesis, such as loss of cell polarity and acquisition of motile properties and mesenchymal phenotype, are associated to deregulated ALK-5 signaling. ALK-5 inhibitors, such as SB505154, GW6604, SD208, and LY2157299, have recently been reported to inhibit ALK-5 autophosphorylation and induce the transcription of matrix genes. Due to their ability to impair cell migration, invasion and metastasis, ALK-5 inhibitors have been explored as worthwhile hits as anticancer agents. This work reports the development of a structure-based virtual screening (SBVS) protocol aimed to prospect promising hits for further studies as novel ALK-5 inhibitors. From a lead-like subset of purchasable compounds, five molecules were identified as putative ALK-5 inhibitors. In addition, molecular dynamics and binding free energy calculations combined with pharmacokinetics and toxicity profiling demonstrated the suitability of these compounds to be further investigated as novel ALK-5 inhibitors.
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Radifar, Muhammad, Nunung Yuniarti, and Enade Perdana Istyastono. "PyPLIF-ASSISTED REDOCKING INDOMETHACIN-(R)-ALPHA-ETHYL-ETHANOLAMIDE INTO CYCLOOXYGENASE-1." Indonesian Journal of Chemistry 13, no. 3 (December 18, 2013): 283–86. http://dx.doi.org/10.22146/ijc.21289.
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Identification of Protein-Ligand Interaction Fingerprints (PLIF) has been performed as the rescoring strategy to identify the best pose for the docked poses of indomethacin-(R)-α-ethyl-etanolamide (IMM) in the binding site of cyclooxygenase-1 (COX-1) from simulations using PLANTS molecular docking software version 1.2 (PLANTS1.2). Instead of using the scoring functions included in the docking software, the strategy presented in this article used external software called PyPLIF that could identify the interactions of the ligand to the amino acid residues in the binding pocket and presents them as binary bitstrings, which subsequently were compared to the interaction bitstrings of the co-crystal ligand pose. The results show that PyPLIF-assisted redocking strategy could select the correct pose much better compared to the pose selection without rescoring. Out of 1000 iterative attempts, PyPLIF-assisted redocking simulations could identify 971 correct poses (more than 95%), while the redocking simulations without PyPLIF could only identify 500 correct poses (50%).These works have also provided us with the initial step of the construction of a valid Structure-Based Virtual Screening (SBVS) protocol to identify COX-1 inhibitors.
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Kaliamurthi, Satyavani, Gurudeeban Selvaraj, Chandrabose Selvaraj, Sanjeev Kumar Singh, Dong-Qing Wei, and Gilles H. Peslherbe. "Structure-Based Virtual Screening Reveals Ibrutinib and Zanubrutinib as Potential Repurposed Drugs against COVID-19." International Journal of Molecular Sciences 22, no. 13 (June 30, 2021): 7071. http://dx.doi.org/10.3390/ijms22137071.
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Coronavirus disease (COVID)-19 is the leading global health threat to date caused by a severe acute respiratory syndrome coronavirus (SARS-CoV-2). Recent clinical trials reported that the use of Bruton’s tyrosine kinase (BTK) inhibitors to treat COVID-19 patients could reduce dyspnea and hypoxia, thromboinflammation, hypercoagulability and improve oxygenation. However, the mechanism of action remains unclear. Thus, this study employs structure-based virtual screening (SBVS) to repurpose BTK inhibitors acalabrutinib, dasatinib, evobrutinib, fostamatinib, ibrutinib, inositol 1,3,4,5-tetrakisphosphate, spebrutinib, XL418 and zanubrutinib against SARS-CoV-2. Molecular docking is conducted with BTK inhibitors against structural and nonstructural proteins of SARS-CoV-2 and host targets (ACE2, TMPRSS2 and BTK). Molecular mechanics-generalized Born surface area (MM/GBSA) calculations and molecular dynamics (MD) simulations are then carried out on the selected complexes with high binding energy. Ibrutinib and zanubrutinib are found to be the most potent of the drugs screened based on the results of computational studies. Results further show that ibrutinib and zanubrutinib could exploit different mechanisms at the viral entry and replication stage and could be repurposed as potential inhibitors of SARS-CoV-2 pathogenesis.
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Lee, Jai Woo, Miguel A. Maria-Solano, Thi Ngoc Lan Vu, Sanghee Yoon, and Sun Choi. "Big data and artificial intelligence (AI) methodologies for computer-aided drug design (CADD)." Biochemical Society Transactions 50, no. 1 (January 25, 2022): 241–52. http://dx.doi.org/10.1042/bst20211240.
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There have been numerous advances in the development of computational and statistical methods and applications of big data and artificial intelligence (AI) techniques for computer-aided drug design (CADD). Drug design is a costly and laborious process considering the biological complexity of diseases. To effectively and efficiently design and develop a new drug, CADD can be used to apply cutting-edge techniques to various limitations in the drug design field. Data pre-processing approaches, which clean the raw data for consistent and reproducible applications of big data and AI methods are introduced. We include the current status of the applicability of big data and AI methods to drug design areas such as the identification of binding sites in target proteins, structure-based virtual screening (SBVS), and absorption, distribution, metabolism, excretion and toxicity (ADMET) property prediction. Data pre-processing and applications of big data and AI methods enable the accurate and comprehensive analysis of massive biomedical data and the development of predictive models in the field of drug design. Understanding and analyzing biological, chemical, or pharmaceutical architectures of biomedical entities related to drug design will provide beneficial information in the biomedical big data era.
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MOKRANI, El Hassen, Abdelhak DJEKRIF, Soumia TENIOU, Yousra NOUADRI, Rym Gouta DEMMAK, Abdelouahab CHIKHI, and Abderrahmane BENSEGUENI. "Virtual screening and drug likeness prediction of new potent TMPRSS2 inhibitors as a potential treatment of COVID-19." South Asian Journal of Experimental Biology 12, no. 4 (August 4, 2022): 533–39. http://dx.doi.org/10.38150/sajeb.12(4).p533-539.
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Transmembrane serine protease 2 (TMPRSS2) is a human protease which plays an important role in the viral life cycle. This enzyme cleaves the spike protein required for Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) viral entry at the host cell. TMPRSS2 inhibitors might limit SARS-CoV-2 infection in the respiratory tract. This work aims at identifying new potent TMPRSS2 inhibitors for anti-SARS CoV-2 drug research. Indeed, Structure-Based Virtual Screening (SBVS) of 13 521 analog compounds to 4-carbamimidamidobenzoic acid,a potent TMPRSS2 inhibitor, was undertaken using FlexX program. Then, the top ranked 1000 compounds were re-scored using Glide Extra Precision (XP) and their binding mode into TMPRSS2 binding site was further analyzed in order to eliminate false positive ones. Finally, drug likeness and toxicity properties of the most promising inhibitors were predicted. Out of these, compounds S1 and S2 showed a higher TMPRSS2 inhibitory potency than that of GBS, the reference molecule. They also were predicted to occupy the entire TMPRSS2 binding site making a rational number of interactions. Still more remarkably, these two compounds were also predicted to have satisfying drug likeness properties, indicating that they might be promising lead compounds for further anti-SARS CoV-2 drug research.
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Mulatsari, Esti, Esti Mumpuni, and Feriza Sandayu. "Penapisan Virtual Senyawa–Senyawa dalam Famili Zingiberaeae sebagai Antiinflamasi Menggunakan Protokol EE_COX2_V.1.0." Jurnal Jamu Indonesia 2, no. 2 (July 31, 2017): 60–67. http://dx.doi.org/10.29244/jji.v2i2.33.
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Berbagai penelitian tentang sifat-sifat anti-inflamasi dan anti-kanker dari berbagai senyawa dalam tanaman familia Zingiberaceae telah dilakukan baik secara in vivo maupun in vitro. Enzim yang diinduksi dan diekspresikan pada sel-sel inflamasi dan kanker dianggap sebagai target obat yang ideal untuk menghambat peradangan dan tumorgenesis, salah satunya adalah enzim siklooksigenase-2 (COX-2). Dalam penelitian ini telah dilakukan penapisan virtual senyawa dalam tanaman Kaemferia galanga, Curcuma domestica Val., Zingiber officinale dan Curcuma xanthorrhiza. Tujuan dari penelitian ini adalah untuk mengetahui aktivitas senyawa-senyawa tersebut sebagai penghambat enzim COX-2 secara in-silico. Penelitian ini menggunakan EE_COX2_V.1.0, protokol Structure Based Virtual Screening (SBVS) yang telah divalidasi oleh Mumpuni et al. 2014. Protokol EE_COX2_V.1.0 menggunakan berbagai aplikasi terintegrasi seperti SPORES, PLANTS, BkChem, OpenBabel dan PyMOL. Elusidasi moda ikatan dilakukan terhadap senyawa representatif aktif dan tidak aktif untuk melihat interaksi asam amino dalam binding site senyawa. Berdasarkan skor ChemPLP sebagai hasil dari simulasi docking yang dilakukan pada 27 senyawa, ada 3 senyawa yang berpotensi aktif dalam menghambat COX-2, senyawa tersebut antara lain 2-butil-3- (4-metoksifenil) -2- asam propenoat dengan 6 residu asam amino aktif, 6-shogaol dengan 10 residu asam amino aktif dan desmetoksikurkumin dengan 4 residu asam amino yang aktif.
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Maruca, Annalisa, Delia Lanzillotta, Roberta Rocca, Antonio Lupia, Giosuè Costa, Raffaella Catalano, Federica Moraca, et al. "Multi-Targeting Bioactive Compounds Extracted from Essential Oils as Kinase Inhibitors." Molecules 25, no. 9 (May 6, 2020): 2174. http://dx.doi.org/10.3390/molecules25092174.
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Essential oils (EOs) are popular in aromatherapy, a branch of alternative medicine that claims their curative effects. Moreover, several studies reported EOs as potential anti-cancer agents by inducing apoptosis in different cancer cell models. In this study, we have considered EOs as a potential resource of new kinase inhibitors with a polypharmacological profile. On the other hand, computational methods offer the possibility to predict the theoretical activity profile of ligands, discovering dangerous off-targets and/or synergistic effects due to the potential multi-target action. With this aim, we performed a Structure-Based Virtual Screening (SBVS) against X-ray models of several protein kinases selected from the Protein Data Bank (PDB) by using a chemoinformatics database of EOs. By evaluating theoretical binding affinity, 13 molecules were detected among EOs as new potential kinase inhibitors with a multi-target profile. The two compounds with higher percentages in the EOs were studied more in depth by means Induced Fit Docking (IFD) protocol, in order to better predict their binding modes taking into account also structural changes in the receptor. Finally, given its good binding affinity towards five different kinases, cinnamyl cinnamate was biologically tested on different cell lines with the aim to verify the antiproliferative activity. Thus, this work represents a starting point for the optimization of the most promising EOs structure as kinase inhibitors with multi-target features.
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Song, Ying-Lian, Shuai-Shuai Liu, Jie Yang, Jiao Xie, Xiang Zhou, Zhi-Bing Wu, Li-Wei Liu, Pei-Yi Wang, and Song Yang. "Discovery of Epipodophyllotoxin-Derived B2 as Promising XooFtsZ Inhibitor for Controlling Bacterial Cell Division: Structure-Based Virtual Screening, Synthesis, and SAR Study." International Journal of Molecular Sciences 23, no. 16 (August 14, 2022): 9119. http://dx.doi.org/10.3390/ijms23169119.
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The emergence of phytopathogenic bacteria resistant to antibacterial agents has rendered previously manageable plant diseases intractable, highlighting the need for safe and environmentally responsible agrochemicals. Inhibition of bacterial cell division by targeting bacterial cell division protein FtsZ has been proposed as a promising strategy for developing novel antibacterial agents. We previously identified 4′-demethylepipodophyllotoxin (DMEP), a naturally occurring substance isolated from the barberry species Dysosma versipellis, as a novel chemical scaffold for the development of inhibitors of FtsZ from the rice blight pathogen Xanthomonas oryzae pv. oryzae (Xoo). Therefore, constructing structure−activity relationship (SAR) studies of DMEP is indispensable for new agrochemical discovery. In this study, we performed a structure−activity relationship (SAR) study of DMEP derivatives as potential XooFtsZ inhibitors through introducing the structure-based virtual screening (SBVS) approach and various biochemical methods. Notably, prepared compound B2, a 4′-acyloxy DMEP analog, had a 50% inhibitory concentration of 159.4 µM for inhibition of recombinant XooFtsZ GTPase, which was lower than that of the parent DMEP (278.0 µM). Compound B2 potently inhibited Xoo growth in vitro (minimum inhibitory concentration 153 mg L−1) and had 54.9% and 48.4% curative and protective control efficiencies against rice blight in vivo. Moreover, compound B2 also showed low toxicity for non-target organisms, including rice plant and mammalian cell. Given these interesting results, we provide a novel strategy to discover and optimize promising bactericidal compounds for the management of plant bacterial diseases.
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Nada, Hossam, Ahmed Elkamhawy, and Kyeong Lee. "Identification of 1H-purine-2,6-dione derivative as a potential SARS-CoV-2 main protease inhibitor: molecular docking, dynamic simulations, and energy calculations." PeerJ 10 (October 7, 2022): e14120. http://dx.doi.org/10.7717/peerj.14120.
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The rapid spread of the coronavirus since its first appearance in 2019 has taken the world by surprise, challenging the global economy, and putting pressure on healthcare systems across the world. The introduction of preventive vaccines only managed to slow the rising death rates worldwide, illuminating the pressing need for developing effective antiviral therapeutics. The traditional route of drug discovery has been known to require years which the world does not currently have. In silico approaches in drug design have shown promising results over the last decade, helping to decrease the required time for drug development. One of the vital non-structural proteins that are essential to viral replication and transcription is the SARS-CoV-2 main protease (Mpro). Herein, using a test set of recently identified COVID-19 inhibitors, a pharmacophore was developed to screen 20 million drug-like compounds obtained from a freely accessible Zinc database. The generated hits were ranked using a structure based virtual screening technique (SBVS), and the top hits were subjected to in-depth molecular docking studies and MM-GBSA calculations over SARS-COV-2 Mpro. Finally, the most promising hit, compound (1), and the potent standard (III) were subjected to 100 ns molecular dynamics (MD) simulations and in silico ADME study. The result of the MD analysis as well as the in silico pharmacokinetic study reveal compound 1 to be a promising SARS-Cov-2 MPro inhibitor suitable for further development.
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GC, Sajina, Catherine Libby, Sixue Zhang, Gloria Benavides, Sarah Scott, Yanjie Li, Anh Tran, et al. "DDIS-24. DECREASE IN GLIOBLASTOMA GROWTH IN VITRO WITH TREATMENT OF NOVEL ANALOGS OF GLUCOSE TRANSPORTER INHIBITORS." Neuro-Oncology 21, Supplement_6 (November 2019): vi68. http://dx.doi.org/10.1093/neuonc/noz175.275.
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Abstract Despite available treatments including surgical resection, radiation and chemotherapy, glioblastoma (GBM) is incurable with rapid recurrence and low median survival rate of just fourteen months. Development of more effective treatments is difficult due to the highly heterogeneous nature of GBM. One aspect of that heterogeneity involves brain tumor initiating cells (BTICs) that have a stem cell-like ability to self-renew. BTICs can readily alter their metabolism and survive in low nutrient environments due in part to increased GLUT3 expression. We believe that the higher expression of GLUT3 in cancer cells compared to non-tumor cells makes it a therapeutic target, although the potential for toxicity must be considered. In recently accepted studies by Libby et al., we reported on two novel GLUT inhibitors identified by structure based virtual screening (SBVS) using a GLUT3 homology model. We are creating a structure-activity relationship profile and seek to increase the potency, selectivity and stability of the GLUT inhibitors. In this study we have tested a number of novel analogs and identified three that have maintained efficacy against BTICs in vitro. Importantly, these compounds display minimal toxicity against human astrocytes. The novel derivatives have increased stability compared to the lead compounds and are efficacious in the nanomolar range. In the future, we intend to utilize our anti-GLUT compounds alone and in combination with radio- and chemotherapy with the hope of clinical translation.
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Schneider, Melanie, Jean-Luc Pons, William Bourguet, and Gilles Labesse. "Towards accurate high-throughput ligand affinity prediction by exploiting structural ensembles, docking metrics and ligand similarity." Bioinformatics 36, no. 1 (July 26, 2019): 160–68. http://dx.doi.org/10.1093/bioinformatics/btz538.
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Abstract Motivation Nowadays, virtual screening (VS) plays a major role in the process of drug development. Nonetheless, an accurate estimation of binding affinities, which is crucial at all stages, is not trivial and may require target-specific fine-tuning. Furthermore, drug design also requires improved predictions for putative secondary targets among which is Estrogen Receptor alpha (ERα). Results VS based on combinations of Structure-Based VS (SBVS) and Ligand-Based VS (LBVS) is gaining momentum to improve VS performances. In this study, we propose an integrated approach using ligand docking on multiple structural ensembles to reflect receptor flexibility. Then, we investigate the impact of the two different types of features (structure-based and ligand molecular descriptors) on affinity predictions using a random forest algorithm. We find that ligand-based features have lower predictive power (rP = 0.69, R2 = 0.47) than structure-based features (rP = 0.78, R2 = 0.60). Their combination maintains high accuracy (rP = 0.73, R2 = 0.50) on the internal test set, but it shows superior robustness on external datasets. Further improvement and extending the training dataset to include xenobiotics, leads to a novel high-throughput affinity prediction method for ERα ligands (rP = 0.85, R2 = 0.71). The presented prediction tool is provided to the community as a dedicated satellite of the @TOME server in which one can upload a ligand dataset in mol2 format and get ligand docked and affinity predicted. Availability and implementation http://edmon.cbs.cnrs.fr. Supplementary information Supplementary data are available at Bioinformatics online.
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Moovarkumudalvan, Balasubramanian, Anupriya Madhukumar Geethakumari, Ramya Ramadoss, Kabir H. Biswas, and Borbala Mifsud. "Structure-Based Virtual Screening and Functional Validation of Potential Hit Molecules Targeting the SARS-CoV-2 Main Protease." Biomolecules 12, no. 12 (November 25, 2022): 1754. http://dx.doi.org/10.3390/biom12121754.
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The recent global health emergency caused by the coronavirus disease 2019 (COVID-19) pandemic has taken a heavy toll, both in terms of lives and economies. Vaccines against the disease have been developed, but the efficiency of vaccination campaigns worldwide has been variable due to challenges regarding production, logistics, distribution and vaccine hesitancy. Furthermore, vaccines are less effective against new variants of the SARS-CoV-2 virus and vaccination-induced immunity fades over time. These challenges and the vaccines’ ineffectiveness for the infected population necessitate improved treatment options, including the inhibition of the SARS-CoV-2 main protease (Mpro). Drug repurposing to achieve inhibition could provide an immediate solution for disease management. Here, we used structure-based virtual screening (SBVS) to identify natural products (from NP-lib) and FDA-approved drugs (from e-Drug3D-lib and Drugs-lib) which bind to the Mpro active site with high-affinity and therefore could be designated as potential inhibitors. We prioritized nine candidate inhibitors (e-Drug3D-lib: Ciclesonide, Losartan and Telmisartan; Drugs-lib: Flezelastine, Hesperidin and Niceverine; NP-lib: three natural products) and predicted their half maximum inhibitory concentration using DeepPurpose, a deep learning tool for drug–target interactions. Finally, we experimentally validated Losartan and two of the natural products as in vitro Mpro inhibitors, using a bioluminescence resonance energy transfer (BRET)-based Mpro sensor. Our study suggests that existing drugs and natural products could be explored for the treatment of COVID-19.
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Afroja, Sohani, Abu Saleh Muhammad Nasim, Md Salauddin Khan, and Mohammad Alamgir Kabir. "Rural-Urban Determinants of Receiving Skilled Birth Attendants among Women in Bangladesh: Evidence from National Survey 2017-18." International Journal of Clinical Practice 2022 (December 8, 2022): 1–10. http://dx.doi.org/10.1155/2022/5426875.
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Background. SBAs (skilled birth attendants) play a crucial role in reducing maternal mortality. The proportion of maternal healthcare in Bangladesh that receives quality care at birth has increased; the reasons for this are unknown. The purpose of this study is to see if there has been a change in the use of specific maternal healthcare indicators in urban and rural areas, as well as significant risk factors. Materials and Methods. The data set was extracted from a nationally representative survey based on a cross-sectional study, the Bangladesh Health and Demographic Survey (BDHS) 2017-18. The frequency distribution reveals the general state of SBAs. To identify the association, we performed the chi-square test. Finally, multiple logistic regression was used to analyse the factors associated with SBAs and determine the degree of SBAs disparity between urban and rural areas. Results. In Bangladesh, 53% of women received SBAs during childbirth, with urban and rural areas receiving 68.1 and 52.2 percent, respectively. Women with secondary (AOR: 1.79, CI: 1.05–3.08) and higher (AOR: 4.18, CI: 2.09–8.50) education were more likely to receive SBAs than women in urban areas who were illiterate. Husband’s education, women’s working status, wealth index, children’s birth order, and number of ANC visit are significant factors in receiving SBSs in both urban and rural areas. Higher educated husbands are 1.83 times (AOR = 1.83, CI: 1.04–3.25, p = 0.037) and 1.82 times (AOR = 1.82, CI: 1.29–2.59, p = 0.001) more likely to attend skilled births than uneducated husbands in both urban and rural areas. Respondents from the richest families are more likely to attend skilled births than those from the poorest families in both urban and rural areas. Conclusion. During delivery, significant risk factors are substantially related to SBAs. More attention must be given to rural and illiterate populations, who are less likely to obtain these services, to minimize maternal and neonatal mortality. Special programs could be developed to raise awareness and facilitate the poor in receiving the basic necessities of maternal care.
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Nath, Virendra, Rohini Ahuja, and Vipin Kumar. "Virtual Screening and In Silico Simulation Analysis for Rapid and Efficient Identification of Novel Natural GPR40 Agonist." Letters in Drug Design & Discovery 17, no. 5 (May 18, 2020): 533–46. http://dx.doi.org/10.2174/1570180815666180914162935.
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Background: Diabetes is the foremost health problem worldwide predisposing to increased mortality and morbidity. The available synthetic drugs have serious side effects and thus, emphasize further need to develop effective medication therapy. GPR40 represents an interesting target for developing novel antidiabetic drug. In the current study, searching of potential natural hit candidate as agonist by using structure based computational approach. Methods: The GPR40 agonistic activity of natural compounds was searched by using Maestro through docking and Molecular Dynamics (MD) simulation application. Virtual screening by using IBScreen library of natural compounds was done and the binding modes of newer natural entity(s) were investigated. Further, MD studies of the GPR40 complex with the most promising hit found in this study justified the stability of these complexes. Results: The silicone chip-based approach recognized the most capable six hits and the ADME prediction aided the exploration of their pharmacokinetic potential. In this study, the obtained hit (ZINC70692253) after the use of exhaustive screening having binding energy -107.501 kcal/mol and root mean square deviation of hGPR40-ZINC70692253 is around 3.5 Å in 20 ns of simulation. Conclusion: Successful application of structure-based computational screening gave a novel candidate from Natural Product library for diabetes treatment. So, Natural compounds may tend to cure diabetes with lesser extent of undesirable effects in comparison to synthetic compounds and these novel screened compounds may show a plausible biological response in the hit to lead finding of drug development process. To the best of our knowledge, this is the first example of the successful application of SBVS to discover novel natural hit compounds using hGPR40.
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Perrone, Maria Grazia, Paola Vitale, Morena Miciaccia, Savina Ferorelli, Antonella Centonze, Roberta Solidoro, Cristina Munzone, et al. "Fluorochrome Selection for Imaging Intraoperative Ovarian Cancer Probes." Pharmaceuticals 15, no. 6 (May 26, 2022): 668. http://dx.doi.org/10.3390/ph15060668.
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The identification and removal of all gross and microscopic tumor to render the patient disease free represents a huge challenge in ovarian cancer treatment. The presence of residual disease is an independent negative prognostic factor. Herein, we describe the synthesis and the “in vitro” evaluation of compounds as cyclooxygenase (COX)-1 inhibitors, the COX-1 isoform being an ovarian cancer biomarker, each bearing fluorochromes with different fluorescence features. Two of these compounds N-[4-(9-dimethylimino-9H-benzo[a]phenoxazin-5-ylamino) butyl]-2-(3,4-bis(4-methoxyphenyl)isoxazol-5-yl)acetamide chloride (RR11) and 3-(6-(4-(2-(3,4-bis(4-methoxyphenyl)isoxazole-5-yl)acetamido)butyl)amino-6-oxohexyl)-2-[7-(1,3-dihydro-1,1-dimethyl-3-ethyl 2H-benz[e]indolin-2-yl-idene)-1,3,5-heptatrienyl]-1,1-dimethyl-3-(6-carboxilato-hexyl)-1H-benz[e]indolium chloride, 23 (MSA14) were found to be potent and selective inhibitors of cyclooxygenase (COX)-1 “in vitro”, and thus were further investigated “in vivo”. The IC50 values were 0.032 and 0.087 µM for RR11 and 23 (MSA 14), respectively, whereas the COX-2 IC50 for RR11 is 2.4 µM while 23 (MSA14) did not inhibit COX-2 even at a 50 µM concentration. Together, this represented selectivity index = 75 and 874, respectively. Structure-based virtual screening (SBVS) performed with the Fingerprints for Ligands and Proteins (FLAP) software allowed both to differentiate highly active compounds from less active and inactive structures and to define their interactions inside the substrate-binding cavity of hCOX1. Fluorescent probes RR11 and 23 (MSA14), were used for preliminary near-infrared (NIR) fluorescent imaging (FLI) in human ovarian cancer (OVCAR-3 and SKOV-3) xenograft models. Surprisingly, a tumor-specific signal was observed for both tested fluorescent probes, even though this signal is not linked to the presence of COX-1.
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Israel, Kai, Christopher Zerres, and Dieter K. Tscheulin. "Presenting hotels in virtual reality: does it influence the booking intention?" Journal of Hospitality and Tourism Technology 10, no. 3 (September 17, 2019): 443–63. http://dx.doi.org/10.1108/jhtt-03-2018-0020.
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Purpose The purpose of this study is to investigate the effects of telepresence while using a smartphone-based virtual reality system (SBVR) to explore a hotel virtually and to determine the influence of this immersive experience on the booking intention of the potential customer. Design/methodology/approach Within the scope of this study, a conceptual research model was developed which covered utilitarian and hedonic aspects of the user experience of SBVRs and showed their relevance for the booking intention. A virtual reality application was programmed especially for the study, in which the test persons were able to virtually explore a hotel complex. A total of 569 people participated in the study. A questionnaire was used for the data collection. The structural equation modelling and hypothesis verification were carried out using the partial least squares method. Findings The immersive feeling of telepresence increases the perceived enjoyment and usefulness of the potential customer. In addition, the user's curiosity is aroused by the telepresence, which also significantly increases the perceived enjoyment as well as the perceived usefulness. The hedonic and utilitarian value of the virtual hotel experience increases the probability that the customer will book the travel accommodation. Research limitations/implications The virtual reality application developed for the study is based on static panoramic images and does not contain audio-visual elements (e.g. sound, video, animation). Audio-visual elements might increase the degree of immersion and could therefore be investigated in future research. Practical implications The results of the study show that the SBVR is a suitable marketing tool to present hotels in an informative and entertaining way, and can thereby increase sales and profits. Originality/value For the first time, this study investigates the potential of SBVRs for the virtual product presentation of hotels and provides empirical evidence that the availability of this innovative form of presentation leads to a higher booking intention.
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Fisher, J., K. P. Schröder, and Robert Connon Smith. "Volume-Limited Spectroscopic Binary Statistics." International Astronomical Union Colloquium 191 (August 2004): 65–66. http://dx.doi.org/10.1017/s0252921100008460.
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AbstractWe derive the period (P), primary mass (m1) and mass ratio (q) distributions of the local population of field binaries by studying a volume-limited sample of 371 spectroscopic binaries (SBs) in the solar neighbourhood d ≤ 100 pc and Mv ≤ 4. The sample was collated using the Batten catalogue, data of R.F. Griffin and the Hipparcos catalogue. The SB2s are used to calibrate a Monte-Carlo approach to the q distribution of SB1s, giving a total q distribution confirming a peak at q ≈ 1. Completenesses and parameter-specific biases are also assessed. A substantial number of systems with intermediate to long periods are found which may have significant consequences for the mass-distribution of WDs.
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Pandey, Pankaj, Kuldeep Roy, Haining Liu, Guoyi Ma, Sara Pettaway, Walid Alsharif, Rama Gadepalli, et al. "Structure-Based Identification of Potent Natural Product Chemotypes as Cannabinoid Receptor 1 Inverse Agonists." Molecules 23, no. 10 (October 13, 2018): 2630. http://dx.doi.org/10.3390/molecules23102630.
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Natural products are an abundant source of potential drugs, and their diversity makes them a rich and viable prospective source of bioactive cannabinoid ligands. Cannabinoid receptor 1 (CB1) antagonists are clinically established and well documented as potential therapeutics for treating obesity, obesity-related cardiometabolic disorders, pain, and drug/substance abuse, but their associated CNS-mediated adverse effects hinder the development of potential new drugs and no such drug is currently on the market. This limitation amplifies the need for new agents with reduced or no CNS-mediated side effects. We are interested in the discovery of new natural product chemotypes as CB1 antagonists, which may serve as good starting points for further optimization towards the development of CB1 therapeutics. In search of new chemotypes as CB1 antagonists, we screened the in silico purchasable natural products subset of the ZINC12 database against our reported CB1 receptor model using the structure-based virtual screening (SBVS) approach. A total of 18 out of 192 top-scoring virtual hits, selected based on structural diversity and key protein–ligand interactions, were purchased and subjected to in vitro screening in competitive radioligand binding assays. The in vitro screening yielded seven compounds exhibiting >50% displacement at 10 μM concentration, and further binding affinity (Ki and IC50) and functional data revealed compound 16 as a potent and selective CB1 inverse agonist (Ki = 121 nM and EC50 = 128 nM) while three other compounds—2, 12, and 18—were potent but nonselective CB1 ligands with low micromolar binding affinity (Ki). In order to explore the structure–activity relationship for compound 16, we further purchased compounds with >80% similarity to compound 16, screened them for CB1 and CB2 activities, and found two potent compounds with sub-micromolar activities. Most importantly, these bioactive compounds represent structurally new natural product chemotypes in the area of cannabinoid research and could be considered for further structural optimization as CB1 ligands.
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Gómez-Ganau, Sergi, Josefa Castillo, Andrés Cervantes, Jesus Vicente de Julián-Ortiz, and Rafael Gozalbes. "Computational Evaluation and In Vitro Validation of New Epidermal Growth Factor Receptor Inhibitors." Current Topics in Medicinal Chemistry 20, no. 18 (August 24, 2020): 1628–39. http://dx.doi.org/10.2174/1568026620666200603122726.
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Background: The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein that acts as a receptor of extracellular protein ligands of the epidermal growth factor (EGF/ErbB) family. It has been shown that EGFR is overexpressed by many tumours and correlates with poor prognosis. Therefore, EGFR can be considered as a very interesting therapeutic target for the treatment of a large variety of cancers such as lung, ovarian, endometrial, gastric, bladder and breast cancers, cervical adenocarcinoma, malignant melanoma and glioblastoma. Methods: We have followed a structure-based virtual screening (SBVS) procedure with a library composed of several commercial collections of chemicals (615,462 compounds in total) and the 3D structure of EGFR obtained from the Protein Data Bank (PDB code: 1M17). The docking results from this campaign were then ranked according to the theoretical binding affinity of these molecules to EGFR, and compared with the binding affinity of erlotinib, a well-known EGFR inhibitor. A total of 23 top-rated commercial compounds displaying potential binding affinities similar or even better than erlotinib were selected for experimental evaluation. In vitro assays in different cell lines were performed. A preliminary test was carried out with a simple and standard quick cell proliferation assay kit, and six compounds showed significant activity when compared to positive control. Then, viability and cell proliferation of these compounds were further tested using a protocol based on propidium iodide (PI) and flow cytometry in HCT116, Caco-2 and H358 cell lines. Results: The whole six compounds displayed good effects when compared with erlotinib at 30 μM. When reducing the concentration to 10μM, the activity of the 6 compounds depends on the cell line used: the six compounds showed inhibitory activity with HCT116, two compounds showed inhibition with Caco-2, and three compounds showed inhibitory effects with H358. At 2 μM, one compound showed inhibiting effects close to those from erlotinib. Conclusion: Therefore, these compounds could be considered as potential primary hits, acting as promising starting points to expand the therapeutic options against a wide range of cancers.
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Almihyawi, Raed A. H., Halah M. H. Al-Hasani, Tabarak Sabah Jassim, Ziyad Tariq Muhseen, Sitong Zhang, and Guang Chen. "Molecular Insights into Binding Mode and Interactions of Structure-Based Virtually Screened Inhibitors for Pseudomonas aeruginosa Multiple Virulence Factor Regulator (MvfR)." Molecules 26, no. 22 (November 11, 2021): 6811. http://dx.doi.org/10.3390/molecules26226811.
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Multi-drug resistance (MDR) bacterial pathogens pose a threat to global health and warrant the discovery of new therapeutic molecules, particularly those that can neutralize their virulence and stop the evolution of new resistant mechanisms. The superbug nosocomial pathogen, Pseudomonas aeruginosa, uses a multiple virulence factor regulator (MvfR) to regulate the expression of multiple virulence proteins during acute and persistent infections. The present study targeted MvfR with the intention of designing novel anti-virulent compounds, which will function in two ways: first, they will block the virulence and pathogenesis P. aeruginosa by disrupting the quorum-sensing network of the bacteria, and second, they will stop the evolution of new resistant mechanisms. A structure-based virtual screening (SBVS) method was used to screen druglike compounds from the Asinex antibacterial library (~5968 molecules) and the comprehensive marine natural products database (CMNPD) (~32 thousand compounds), against the ligand-binding domain (LBD) of MvfR, to identify molecules that show high binding potential for the relevant pocket. In this way, two compounds were identified: Top-1 (4-((carbamoyloxy)methyl)-10,10-dihydroxy-2,6-diiminiodecahydropyrrolo[1,2-c]purin-9-yl sulfate) and Top-2 (10,10-dihydroxy-2,6-diiminio-4-(((sulfonatocarbamoyl)oxy)methyl)decahydropyrrolo[1,2-c]purin-9-yl sulfate), in contrast to the co-crystallized M64 control. Both of the screened leads were found to show deep pocket binding and interactions with several key residues through a network of hydrophobic and hydrophilic interactions. The docking results were validated by a long run of 200 ns of molecular dynamics simulation and MM-PB/GBSA binding free energies. All of these analyses confirmed the presence of strong complex formation and rigorous intermolecular interactions. An additional analysis of normal mode entropy and a WaterSwap assay were also performed to complement the aforementioned studies. Lastly, the compounds were found to show an acceptable range of pharmacokinetic properties, making both compounds potential candidates for further experimental studies to decipher their real biological potency.
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Ganapathi, Karthik A., Karyn M. Austin, Maggie Malsch, and Akiko Shimamura. "SBDS Protein Plays a Role in Ribosome Biogenesis." Blood 108, no. 11 (November 16, 2006): 185. http://dx.doi.org/10.1182/blood.v108.11.185.185.
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Abstract Shwachman-Diamond syndrome is an autosomal recessive disorder characterized by exocrine pancreatic insufficiency, bone marrow failure, and leukemia predisposition. The majority of patients with Shwachman-Diamond syndrome harbor mutations in the SBDS gene. SBDS is a novel gene of unknown function and is highly conserved throughout evolution. Studies of the yeast orthologue, YLR022c/SDO1, suggest that SBDS may play a role in ribosome biogenesis. In support of this hypothesis, we have found that the SBDS protein shuttles in and out of the nucleolus. Previously we have shown that SBDS nucleolar localization is regulated in a cell cycle-dependant manner. We now find that SBDS nucleolar localization is also lost following exposure to actinomycin D, suggesting that SBDS nucleolar localization is dependent on active ribosomal RNA (rRNA) transcription. In cell survival assays, SBDS−/− patient-derived cells are sensitive to actinomycin D treatment relative to normal control cells. Introduction of the wild-type SBDS cDNA into SBDS−/− cells corrects their actinomycin D sensitivity, confirming that the observed sensitivity is SBDS-dependent. In contrast, SBDS−/− cells do not exhibit increased sensitivity to cyclohexamide, a protein translation inhibitor. Consistent with this result, SBDS protein co-localizes with ribosomal precursor subunits but not with mature polysomes upon sucrose gradient sedimentation. No differences in polysome profiles are observed between SBDS−/− cells and wild type control cells. Gel filtration studies suggest that SBDS associates into a complex with other proteins. SBDS co-immunoprecipitates with other nucleolar proteins involved in rRNA biogenesis. RNA immunoprecipitation studies reveal that SBDS also associates with the 28S rRNA but not the 18S rRNA. These findings support the hypothesis that SBDS plays a role in ribosome biogenesis
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Neri, Giuseppe, Giovanni Arpa, Camilla Guerini, Federica Grillo, Marco Vincenzo Lenti, Paolo Giuffrida, Daniela Furlan, et al. "Small Bowel Adenocarcinomas Featuring Special AT-Rich Sequence-Binding Protein 2 (SATB2) Expression and a Colorectal Cancer-Like Immunophenotype: A Potential Diagnostic Pitfall." Cancers 12, no. 11 (November 19, 2020): 3441. http://dx.doi.org/10.3390/cancers12113441.
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Special AT-rich sequence-binding protein 2 (SATB2) is a transcription factor expressed by colonic cryptic epithelium and epithelial neoplasms of the lower gastrointestinal (GI) tract, as well as by small bowel adenocarcinomas (SBAs), though at a lower rate. Nevertheless, up to now, only small SBA series, often including a very limited number of Crohn’s disease-associated SBAs (CrD-SBAs) and celiac disease-associated SBAs (CD-SBA), have been investigated for SATB2 expression. We evaluated the expression of SATB2 and other GI phenotypic markers (cytokeratin (CK) 7 and CK20, caudal type homeobox 2 (CDX2) and alpha-methylacyl-CoA racemase (AMACR)), as well as mismatch repair (MMR) proteins, in 100 SBAs, encompassing 34 CrD-SBAs, 28 CD-SBAs and 38 sporadic cases (Spo-SBAs). Any mutual association and correlation with other clinico-pathologic features, including patient prognosis, were searched. Twenty (20%) SATB2-positive SBAs (4 CrD-SBAs, 7 CD-SBAs and 9 Spo-SBAs) were identified. The prevalence of SATB2 positivity was lower in CrD-SBA (12%) in comparison with both CD-SBAs (25%) and Spo-SBAs (24%). Interestingly, six SBAs (two CD-SBAs and four Spo-SBAs) displayed a full colorectal carcinoma (CRC)-like immunoprofile (CK7−/CK20+/CDX2+/AMACR+/SATB2+); none of them was a CrD-SBA. No association between SATB2 expression and MMR status was observed. Although SATB2-positive SBA patients showed a more favorable outcome in comparison with SATB2-negative ones, the difference did not reach statistical significance. When cancers were stratified according to CK7/CK20 expression patterns, we found that CK7−/CK20- SBAs were enriched with MMR-deficient cases (71%) and patients with CK7−/CK20− or CK7−/CK20+ SBAs had a significantly better survival rate compared to those with CK7+/CK20− or CK7+/CK20+ cancers (p = 0.002). To conclude, we identified a small (6%) subset of SBAs featuring a full CRC-like immunoprofile, representing a potential diagnostic pitfall in attempts to identify the site of origin of neoplasms of unknown primary site. In contrast with data on colorectal carcinoma, SATB2 expression is not associated with MMR status in SBAs. CK patterns influence patient survival, as CK7−/CK20− cancers show better prognosis, a behavior possibly due to the high rate of MMR-deficient SBAs within this subgroup.
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Xu, Chao, Bangrang Di, and Jianxin Wei. "A physical modeling study of seismic features of karst cave reservoirs in the Tarim Basin, China." GEOPHYSICS 81, no. 1 (January 1, 2016): B31—B41. http://dx.doi.org/10.1190/geo2014-0548.1.
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On seismic migration sections, anomalous bright spots, called the string of beads response (SBR), are common features of carbonate karst reservoirs at the seismic scale in the Tarim Basin, China. To understand the SBR features of different karst caves, which is an important issue for local exploration, we conducted a physical modeling experiment. Within the physical model, we included various single caves with different scales, velocities, shapes, and fluids, as well as multiple caves in different spatial distributions. SBRs of all caves were extracted and summarized from the migration sections. First, we investigated effects of the cave scale, velocity, spatial distribution, shape, and fluids on SBRs. The relative amplitude of SBRs increased with the cave width ranging from 25 to 400 m and decreased with the cave velocity. The SBR split into two new SBRs when the cave height was larger than 100 m. Spatially distributed multiple caves resulted in some special SBRs, such as long SBRs, inclined SBRs, waved SBRs, and chaotic SBRs. The cave shape contribution to SBRs could be neglected in deep strata practically. The relative amplitude of SBRs of caves filled with gas and oil was stronger than those filled with water. Then, we established an interpretation chart of the corresponding relationship between six types of SBRs and their potential caves. Short SBRs were the responses of caves with a height of less than 60 m. Long SBRs corresponded to two kinds of cave units: (1) a single cave with a height between 70 and 100 m and (2) two caves (height less than 60 m) vertically distributed with a small distance (less than 60 m). Chop-shaped SBRs indicated caves with a width of more than 100 m. Inclined SBRs, waved SBRs, and chaotic SBRs corresponded to multiple caves spatially distributed in triangles, rhombuses, and clusters, respectively.
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Che, Wenqiang, Jie Liu, Tengyue Fu, Xiangyu Wang, and Jun Lyu. "Recent Trends in Synchronous Brain Metastasis Incidence and Mortality in the United States: Ten-Year Multicenter Experience." Current Oncology 29, no. 11 (November 2, 2022): 8374–89. http://dx.doi.org/10.3390/curroncol29110660.
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Background: Large epidemiological studies describing the trends in incidence rates and mortality of synchronous brain metastases (SBMs) are lacking. The study aimed to provide a comprehensive understanding of the changes in the incidence and mortality of SBMs over the previous ten years. Methods: Trends in the incidence of solid malignancies outside of the CNS in patients with SBMs and incidence-based mortality rates were assessed using data from the Surveillance, Epidemiology, and End Results database. Joinpoint analyses were used to calculate annual percent changes (APCs) and 95% CIs. Results: Between 2010 and 2019, 66,655 patients, including 34,821 (52.24%) men and 31,834 (47.76%) women, were found to have SBMs, and 57,692 deaths occurred over this period. Lung cancer SBMs, melanoma SBMs, and breast cancer SBMs were ranked in the top three, having the highest age-standardized incidence rates. The incidence of SBMs decreased significantly with an APC of −0.6% from 2010 to 2019, while the APC was 1.2% for lung cancer SBMs, 2.5% for melanoma SBMs, and 0.6% for breast cancer SBMs. The SBM mortality first experienced a rapid increase (APC = 28.6%) from 2010 to 2012 and then showed a significant decline at an APC of −1.8% from 2012 to 2019. Lung cancer SBMs showed similar trends, while melanoma SBM and breast cancer SBM mortality increased continuously. Conclusions: SBMs incidence (2010–2019) and incidence-based mortality (2012–2019) declined significantly. These findings can advance our understanding of the prevalence of SBMs.
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Wang, Hao, Kim Fung Tsang, Chung Kit Wu, Yang Wei, Yucheng Liu, and Chun Sing Lai. "IEEE P2668 Compatible Evaluation Strategy for Smart Battery Management Systems." Sensors 22, no. 16 (August 13, 2022): 6057. http://dx.doi.org/10.3390/s22166057.
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In smart cities and smart industry, a Battery Management System (BMS) focuses on the intelligent supervision of the status (e.g., state of charge, temperature) of batteries (e.g., lithium battery, lead battery). Internet of Things (IoT) integration enhances the system’s intelligence and convenience, making it a Smart BMS (SBMS). However, this also raises concerns regarding evaluating the SBMS in the wireless context in which these systems are installed. Considering the battery application, in particular, the SBMS will depend on several wireless communication characteristics, such as mobility, latency, fading, etc., necessitating a tailored evaluation strategy. This study proposes an IEEE P2668-Compatible SBMS Evaluation Strategy (SBMS-ES) to overcome this issue. The SBMS-ES is based on the IEEE P2668 worldwide standard, which aims to assess IoT solutions’ maturity. It evaluates the characteristics of the wireless environment for SBMS while considering battery factors. The SBMS-ES scores the candidates under numerous scenarios with various characteristics. A final score between 0 and 5 is given to indicate the performance of the SBMS regarding the application demands. The disadvantages of the SBMS solution and the most desired candidate can be found with the evaluated score. SBMS-ES provides guidance to avoid potential risks and mitigates the issues posed by an inadequate or unsatisfactory SBMS solution. A case study is depicted for illustration.
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Eschenröder, Tjark C. "Secondary Buyout Performance." Zeitschrift für Bankrecht und Bankwirtschaft 32, no. 1 (February 18, 2020): 36–58. http://dx.doi.org/10.15375/zbb-2020-0106.
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AbstractThere is an ambivalent discussion about the performance of secondary buyouts (SBOs): Private equity (PE) sponsors often assume an underperformance of SBOs compared to primary buyouts (PBOs). However, the share of SBOs grew significantly to more than 50 percent of all buyouts in 2018. This paper contributes to solve this apparent contradiction. It analyses the performance of SBOs compared to PBOs based on a dataset of 295 UK portfolio companies which underwent back-to-back buyout rounds. The analysis of the total sample shows that SBOs perform worse or at least not better than PBOs. A more detailed analysis of subsamples reveals that SBOs may be attractive PE targets: The underperformance is driven by size and time effects. SBOs perform worse at growing small and medium-sized portfolio companies and are inferior at developing the profitability of medium-sized companies. Interestingly, the underperformance diminishes in the course of time; SBOs do not perform differently compared to PBOs for the time after the financial crises. Considering the limited supply of investment opportunities for PBOs, I find that well-chosen SBOs outperform the remaining, low performing PBOs. Therefore, SBOs are not means of last resort for PE firms. SBOs have a promising potential of value creation, which may partly explain the significant growth of SBO deals.