Virtual screening on the web for drug repurposing: a primer

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Abstract

We describe a procedure of performing in silico (virtual) screening using a web-based service, the MTiOpenScreen, which
is freely accessible to non-commercial users. We shall use the SARS-CoV-2 main protease as an example. Starting from a structure downloaded from the Protein Data Bank, we discuss how to prepare the coordinates file, taking into account the known biochemical background information of the target protein. The reader will find that this preparation step takes up most of the effort before the target is ready for screening. The steps for uploading the target structure and defining the search volume by critical residues, and the main parameters to use, are outlined. When this protocol is followed, the user will expect to obtain a ranked list of small approved drug compounds docked into the target structure. The results can be readily examined graphically on the web site or downloaded for studying in a local molecular graphics program such as PyMOL.

References

1. Chen YW, Yiu CB, Wong K. (2020) Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL pro) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates. F1000Res 9: 129. doi: 10.12688/f1000research.22457.2. PMID: 32194944
2. Labbé CM, Rey J, Lagorce D, Vavruša M, Becot J, et al. (2015) MTiOpenScreen: a web server for structure-based virtual screening. Nucleic Acids Res 43: doi: 10.1093/nar/gkv306. PMID: 25855812
3. Lagarde N, Rey J, Gyulkhandanyan A, Tufféry P, Miteva MA, et al. (2018) Online structure-based screening of purchasable approved drugs and natural compounds: retrospective examples of drug repositioning on cancer targets. Oncotarget 9: 32346-32361. doi: 10.18632/oncotarget.25966. PMID: 30190791
4. The PyMOL molecular graphics system. Schrödinger LLC. Version 1.7 or later. Available from: https://pymolwiki.org/index.php/Linux_Install
5. Emsley P, Lohkamp B, Scott WG, Cowtan K. (2010) Features and development of Coot. Acta Crystallogr D Biol Crystallogr 66: 486-501. doi: 10.1107/S0907444910007493. PMID: 20383002
6. Trott O, Olson AJ. (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31: 455-461. doi: 10.1002/jcc.21334. PMID: 19499576
7. Winn MD, Ballard CC, Cowtan KD, Dodson EJ, Emsley P, et al. (2011) Overview of the CCP4 suite and current developments. Acta Crystallogr D Biol Crystallogr 67: 235-242. doi: 10.1107/S0907444910045749. PMID: 21460441
8. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, et al. (2000) The Protein Data Bank. Nucleic Acids Res 28: 235-242. doi: 10.1093/nar/28.1.235. PMID: 10592235
9. Muramatsu T, Takemoto C, Kim Y, Wang H, Nishii W, et al. (2016) SARS-CoV 3CL protease cleaves its C-terminal autoprocessing site by novel subsite cooperativity. Proc Natl Acad Sci U S A 113: 12997-13002. doi: 10.1073/pnas.1601327113. PMID: 27799534
10. Jaghoori MM, Bleijlevens B, Olabarriaga SD. (2016) 1001 Ways to run AutoDock Vina for virtual screening. J Comput Aided Mol Des 30: 237-249. doi: 10.1007/s10822-016-9900-9. PMID: 26897747
11. Quiroga R, Villarreal MA. (2016) Vinardo: A Scoring Function Based on Autodock Vina Improves Scoring, Docking, and Virtual Screening. PLoS One 11: doi: 10.1371/journal.pone.0155183. PMID: 27171006
12. Singh N, Decroly E, Khatib A, Villoutreix BO. (2020) Structure-based drug repositioning over the human TMPRSS2 protease domain: search for chemical probes able to repress SARS-CoV-2 Spike protein cleavages. Eur J Pharm Sci 153: 105495. doi: 10.1016/j.ejps.2020.105495. PMID: 32730844
13. Yang H, Yang M, Ding Y, Liu Y, Lou Z, et al. (2003) The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor. Proc Natl Acad Sci USA 100: 13190-13195. doi: 10.1073/pnas.1835675100. PMID: 14585926
14. Jin Z, Du X, Xu Y, Deng Y, Liu M, et al. (2020) Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature 582: 289-293. doi: 10.1038/s41586-020-2223-y. PMID: 32272481
15. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, et al. (2020) A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 583: 459-468. doi: 10.1038/s41586-020-2286-9. PMID: 32353859

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