Discovery of Small-Molecule Inhibitors of SARS-CoV-2 Proteins Using a Computational and Experimental Pipeline

Frontiers in Molecular Biosciences

Hyojin Kim¹  Marisa W. Torres²  Derek Jones²  Jonathan E. Allen²  Adam Zemla²  Aidan Epstein²  Stewart He²  Kevin McLoughlin²  Garrett A. Stevenson³  Feliza Bourguet⁴  Felice C. Lightstone⁴  Monica Borucki⁴  Dina R. Weilhammer⁴  Edmond Y. Lau⁴  Jacky Lo⁴  Victoria Lao⁴  Brian J. Bennion⁴  Brent Segelke⁴  Yue Yang⁴  Daniel Kirshner⁴  Fangqiang Zhu⁴  W. F. Drew Bennett⁴  Magdalena Franco⁴  Deepa K. Murugesh⁴  Sergio Wong⁴  Xiaohua Zhang⁴  Brooke Harmon⁵  Richard Mosesso⁵  Edwin A. Saada⁵  Maxwell A. Stefan⁵  Oscar A. Negrete⁶ 

[1] Lawrence Livermore National Laboratory, Computing Directorate, Center for Applied Scientific Computing, Livermore, CA, United States;Lawrence Livermore National Laboratory, Computing Directorate, Global Security Computing Division, Livermore, CA, United States;Lawrence Livermore National Laboratory, Engineering Directorate, Computational Engineering Division, Livermore, CA, United States;Lawrence Livermore National Laboratory, Physical and Life Sciences Directorate, Biotechnology and Biosciences Division, Livermore, CA, United States;Sandia National Laboratory, Department Systems Biology, Livermore, CA, United States;Sandia National Laboratory, Department of Biotechnologies and Bioengineering, Livermore, CA, United States;

关键词: COVID-19;    molecular simulations;    machine-learning;    protein assays;    FRET;    live virus;   

DOI  :  10.3389/fmolb.2021.678701

来源: DOAJ

【 摘 要 】

A rapid response is necessary to contain emergent biological outbreaks before they can become pandemics. The novel coronavirus (SARS-CoV-2) that causes COVID-19 was first reported in December of 2019 in Wuhan, China and reached most corners of the globe in less than two months. In just over a year since the initial infections, COVID-19 infected almost 100 million people worldwide. Although similar to SARS-CoV and MERS-CoV, SARS-CoV-2 has resisted treatments that are effective against other coronaviruses. Crystal structures of two SARS-CoV-2 proteins, spike protein and main protease, have been reported and can serve as targets for studies in neutralizing this threat. We have employed molecular docking, molecular dynamics simulations, and machine learning to identify from a library of 26 million molecules possible candidate compounds that may attenuate or neutralize the effects of this virus. The viability of selected candidate compounds against SARS-CoV-2 was determined experimentally by biolayer interferometry and FRET-based activity protein assays along with virus-based assays. In the pseudovirus assay, imatinib and lapatinib had IC50 values below 10 μM, while candesartan cilexetil had an IC50 value of approximately 67 µM against Mpro in a FRET-based activity assay. Comparatively, candesartan cilexetil had the highest selectivity index of all compounds tested as its half-maximal cytotoxicity concentration 50 (CC50) value was the only one greater than the limit of the assay (>100 μM).

【 授权许可】

Unknown