Frontiers in Molecular Biosciences (Jul 2021)
Discovery of Small-Molecule Inhibitors of SARS-CoV-2 Proteins Using a Computational and Experimental Pipeline
- Edmond Y. Lau,
- Oscar A. Negrete,
- W. F. Drew Bennett,
- Brian J. Bennion,
- Monica Borucki,
- Feliza Bourguet,
- Aidan Epstein,
- Magdalena Franco,
- Brooke Harmon,
- Stewart He,
- Derek Jones,
- Hyojin Kim,
- Daniel Kirshner,
- Victoria Lao,
- Jacky Lo,
- Kevin McLoughlin,
- Richard Mosesso,
- Deepa K. Murugesh,
- Edwin A. Saada,
- Brent Segelke,
- Maxwell A. Stefan,
- Garrett A. Stevenson,
- Marisa W. Torres,
- Dina R. Weilhammer,
- Sergio Wong,
- Yue Yang,
- Adam Zemla,
- Xiaohua Zhang,
- Fangqiang Zhu,
- Jonathan E. Allen,
- Felice C. Lightstone
Affiliations
- Edmond Y. Lau
- Lawrence Livermore National Laboratory, Physical and Life Sciences Directorate, Biotechnology and Biosciences Division, Livermore, CA, United States
- Oscar A. Negrete
- Sandia National Laboratory, Department of Biotechnologies and Bioengineering, Livermore, CA, United States
- W. F. Drew Bennett
- Lawrence Livermore National Laboratory, Physical and Life Sciences Directorate, Biotechnology and Biosciences Division, Livermore, CA, United States
- Brian J. Bennion
- Lawrence Livermore National Laboratory, Physical and Life Sciences Directorate, Biotechnology and Biosciences Division, Livermore, CA, United States
- Monica Borucki
- Lawrence Livermore National Laboratory, Physical and Life Sciences Directorate, Biotechnology and Biosciences Division, Livermore, CA, United States
- Feliza Bourguet
- Lawrence Livermore National Laboratory, Physical and Life Sciences Directorate, Biotechnology and Biosciences Division, Livermore, CA, United States
- Aidan Epstein
- Lawrence Livermore National Laboratory, Computing Directorate, Global Security Computing Division, Livermore, CA, United States
- Magdalena Franco
- Lawrence Livermore National Laboratory, Physical and Life Sciences Directorate, Biotechnology and Biosciences Division, Livermore, CA, United States
- Brooke Harmon
- Sandia National Laboratory, Department Systems Biology, Livermore, CA, United States
- Stewart He
- Lawrence Livermore National Laboratory, Computing Directorate, Global Security Computing Division, Livermore, CA, United States
- Derek Jones
- Lawrence Livermore National Laboratory, Computing Directorate, Global Security Computing Division, Livermore, CA, United States
- Hyojin Kim
- Lawrence Livermore National Laboratory, Computing Directorate, Center for Applied Scientific Computing, Livermore, CA, United States
- Daniel Kirshner
- Lawrence Livermore National Laboratory, Physical and Life Sciences Directorate, Biotechnology and Biosciences Division, Livermore, CA, United States
- Victoria Lao
- Lawrence Livermore National Laboratory, Physical and Life Sciences Directorate, Biotechnology and Biosciences Division, Livermore, CA, United States
- Jacky Lo
- Lawrence Livermore National Laboratory, Physical and Life Sciences Directorate, Biotechnology and Biosciences Division, Livermore, CA, United States
- Kevin McLoughlin
- Lawrence Livermore National Laboratory, Computing Directorate, Global Security Computing Division, Livermore, CA, United States
- Richard Mosesso
- Sandia National Laboratory, Department Systems Biology, Livermore, CA, United States
- Deepa K. Murugesh
- Lawrence Livermore National Laboratory, Physical and Life Sciences Directorate, Biotechnology and Biosciences Division, Livermore, CA, United States
- Edwin A. Saada
- Sandia National Laboratory, Department Systems Biology, Livermore, CA, United States
- Brent Segelke
- Lawrence Livermore National Laboratory, Physical and Life Sciences Directorate, Biotechnology and Biosciences Division, Livermore, CA, United States
- Maxwell A. Stefan
- Sandia National Laboratory, Department Systems Biology, Livermore, CA, United States
- Garrett A. Stevenson
- Lawrence Livermore National Laboratory, Engineering Directorate, Computational Engineering Division, Livermore, CA, United States
- Marisa W. Torres
- Lawrence Livermore National Laboratory, Computing Directorate, Global Security Computing Division, Livermore, CA, United States
- Dina R. Weilhammer
- Lawrence Livermore National Laboratory, Physical and Life Sciences Directorate, Biotechnology and Biosciences Division, Livermore, CA, United States
- Sergio Wong
- Lawrence Livermore National Laboratory, Physical and Life Sciences Directorate, Biotechnology and Biosciences Division, Livermore, CA, United States
- Yue Yang
- Lawrence Livermore National Laboratory, Physical and Life Sciences Directorate, Biotechnology and Biosciences Division, Livermore, CA, United States
- Adam Zemla
- Lawrence Livermore National Laboratory, Computing Directorate, Global Security Computing Division, Livermore, CA, United States
- Xiaohua Zhang
- Lawrence Livermore National Laboratory, Physical and Life Sciences Directorate, Biotechnology and Biosciences Division, Livermore, CA, United States
- Fangqiang Zhu
- Lawrence Livermore National Laboratory, Physical and Life Sciences Directorate, Biotechnology and Biosciences Division, Livermore, CA, United States
- Jonathan E. Allen
- Lawrence Livermore National Laboratory, Computing Directorate, Global Security Computing Division, Livermore, CA, United States
- Felice C. Lightstone
- Lawrence Livermore National Laboratory, Physical and Life Sciences Directorate, Biotechnology and Biosciences Division, Livermore, CA, United States
- DOI
- https://doi.org/10.3389/fmolb.2021.678701
- Journal volume & issue
-
Vol. 8
Abstract
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).
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