• Vikash Kumar, Haiguang Liu, and Chun Wu.
• Complex Systems Division, Beijing Computational Science Research Center, Haidian District, Beijing, 100193, China.
• Comput. Biol. Med. 2021 Aug 1; 135: 104634.

AbstractSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused worldwide pandemic and is responsible for millions of worldwide deaths due to -a respiratory disease known as COVID-19. In the search for a cure of COVID-19, drug repurposing is a fast and cost-effective approach to identify anti-COVID-19 drugs from existing drugs. The receptor binding domain (RBD) of the SARS-CoV-2 spike protein has been a main target for drug designs to block spike protein binding to ACE2 proteins. In this study, we probed the conformational plasticity of the RBD using long molecular dynamics (MD) simulations, from which, representative conformations were identified using clustering analysis. Three simulated conformations and the original crystal structure were used to screen FDA approved drugs (2466 drugs) against the predicted binding site at the ACE2-RBD interface, leading to 18 drugs with top docking scores. Notably, 16 out of the 18 drugs were obtained from the simulated conformations, while the crystal structure suggests poor binding. The binding stability of the 18 drugs were further investigated using MD simulations. Encouragingly, 6 drugs exhibited stable binding with RBD at the ACE2-RBD interface and 3 of them (gonadorelin, fondaparinux and atorvastatin) showed significantly enhanced binding after the MD simulations. Our study shows that flexibility modeling of SARS-CoV-2 RBD using MD simulation is of great help in identifying novel agents which might block the interaction between human ACE2 and the SARS-CoV-2 RBD for inhibiting the virus infection.Copyright © 2021. Published by Elsevier Ltd.

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