Rapid Identification of Potential Inhibitors of SARS-CoV-2 Main Protease by Deep Docking of 1.3 Billion Compounds

Overview

Journal Mol Inform

Specialties Biochemistry
Biology
Chemistry
Molecular Biology

Date 2020 Mar 13

PMID 32162456

Citations 226

Authors

Anh-Tien Ton

Francesco Gentile

Michael Hsing

Fuqiang Ban

Artem Cherkasov

Affiliations

Soon will be listed here.

Abstract

The recently emerged 2019 Novel Coronavirus (SARS-CoV-2) and associated COVID-19 disease cause serious or even fatal respiratory tract infection and yet no approved therapeutics or effective treatment is currently available to effectively combat the outbreak. This urgent situation is pressing the world to respond with the development of novel vaccine or a small molecule therapeutics for SARS-CoV-2. Along these efforts, the structure of SARS-CoV-2 main protease (Mpro) has been rapidly resolved and made publicly available to facilitate global efforts to develop novel drug candidates. Recently, our group has developed a novel deep learning platform - Deep Docking (DD) which provides fast prediction of docking scores of Glide (or any other docking program) and, hence, enables structure-based virtual screening of billions of purchasable molecules in a short time. In the current study we applied DD to all 1.3 billion compounds from ZINC15 library to identify top 1,000 potential ligands for SARS-CoV-2 Mpro protein. The compounds are made publicly available for further characterization and development by scientific community.

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References

Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M . Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020; 30(3):269-271. PMC: 7054408. DOI: 10.1038/s41422-020-0282-0. View

Blanchard J, Elowe N, Huitema C, Fortin P, Cechetto J, Eltis L . High-throughput screening identifies inhibitors of the SARS coronavirus main proteinase. Chem Biol. 2004; 11(10):1445-53. PMC: 7134594. DOI: 10.1016/j.chembiol.2004.08.011. View

Lyu J, Wang S, Balius T, Singh I, Levit A, Moroz Y . Ultra-large library docking for discovering new chemotypes. Nature. 2019; 566(7743):224-229. PMC: 6383769. DOI: 10.1038/s41586-019-0917-9. View

Muramatsu T, Takemoto C, Kim Y, Wang H, Nishii W, Terada T . SARS-CoV 3CL protease cleaves its C-terminal autoprocessing site by novel subsite cooperativity. Proc Natl Acad Sci U S A. 2016; 113(46):12997-13002. PMC: 5135343. DOI: 10.1073/pnas.1601327113. View

Zhang H, Liao L, Saravanan K, Yin P, Wei Y . DeepBindRG: a deep learning based method for estimating effective protein-ligand affinity. PeerJ. 2019; 7:e7362. PMC: 6661145. DOI: 10.7717/peerj.7362. View

Yang H, Yang M, Ding Y, Liu Y, Lou Z, Zhou Z . The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor. Proc Natl Acad Sci U S A. 2003; 100(23):13190-5. PMC: 263746. DOI: 10.1073/pnas.1835675100. View

Song Z, Xu Y, Bao L, Zhang L, Yu P, Qu Y . From SARS to MERS, Thrusting Coronaviruses into the Spotlight. Viruses. 2019; 11(1). PMC: 6357155. DOI: 10.3390/v11010059. View

Pillaiyar T, Manickam M, Namasivayam V, Hayashi Y, Jung S . An Overview of Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy. J Med Chem. 2016; 59(14):6595-628. PMC: 7075650. DOI: 10.1021/acs.jmedchem.5b01461. View

Ashtawy H, Mahapatra N . A Comparative Assessment of Predictive Accuracies of Conventional and Machine Learning Scoring Functions for Protein-Ligand Binding Affinity Prediction. IEEE/ACM Trans Comput Biol Bioinform. 2015; 12(2):335-47. DOI: 10.1109/TCBB.2014.2351824. View

10.

Han D, Penn-Nicholson A, Cho M . Identification of critical determinants on ACE2 for SARS-CoV entry and development of a potent entry inhibitor. Virology. 2006; 350(1):15-25. PMC: 7111894. DOI: 10.1016/j.virol.2006.01.029. View

11.

Lee H, Mittal A, Patel K, Gatuz J, Truong L, Torres J . Identification of novel drug scaffolds for inhibition of SARS-CoV 3-Chymotrypsin-like protease using virtual and high-throughput screenings. Bioorg Med Chem. 2013; 22(1):167-77. PMC: 3971864. DOI: 10.1016/j.bmc.2013.11.041. View

12.

Das P, Puusepp L, Varghese F, Utt A, Ahola T, Kananovich D . Design and Validation of Novel Chikungunya Virus Protease Inhibitors. Antimicrob Agents Chemother. 2016; 60(12):7382-7395. PMC: 5119020. DOI: 10.1128/AAC.01421-16. View

13.

Berry M, Fielding B, Gamieldien J . Potential Broad Spectrum Inhibitors of the Coronavirus 3CLpro: A Virtual Screening and Structure-Based Drug Design Study. Viruses. 2015; 7(12):6642-60. PMC: 4690886. DOI: 10.3390/v7122963. View

14.

Turk B . Targeting proteases: successes, failures and future prospects. Nat Rev Drug Discov. 2006; 5(9):785-99. DOI: 10.1038/nrd2092. View

15.

Zumla A, Chan J, Azhar E, Hui D, Yuen K . Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016; 15(5):327-47. PMC: 7097181. DOI: 10.1038/nrd.2015.37. View

16.

Zhang H, Saravanan K, Yang Y, Hossain M, Li J, Ren X . Deep Learning Based Drug Screening for Novel Coronavirus 2019-nCov. Interdiscip Sci. 2020; 12(3):368-376. PMC: 7266118. DOI: 10.1007/s12539-020-00376-6. View

17.

Pagadala N, Syed K, Tuszynski J . Software for molecular docking: a review. Biophys Rev. 2017; 9(2):91-102. PMC: 5425816. DOI: 10.1007/s12551-016-0247-1. View

18.

Cameron C, Castro C . The mechanism of action of ribavirin: lethal mutagenesis of RNA virus genomes mediated by the viral RNA-dependent RNA polymerase. Curr Opin Infect Dis. 2002; 14(6):757-64. DOI: 10.1097/00001432-200112000-00015. View

19.

Mysinger M, Carchia M, Irwin J, Shoichet B . Directory of useful decoys, enhanced (DUD-E): better ligands and decoys for better benchmarking. J Med Chem. 2012; 55(14):6582-94. PMC: 3405771. DOI: 10.1021/jm300687e. View

20.

Berman H, Westbrook J, Feng Z, Gilliland G, Bhat T, Weissig H . The Protein Data Bank. Nucleic Acids Res. 1999; 28(1):235-42. PMC: 102472. DOI: 10.1093/nar/28.1.235. View