Drug repurposing against SARS-CoV-2 receptor binding domain using ensemble-based virtual screening and molecular dynamics simulations. (August 2021)

• Record Type: Journal Article
• Authors: Kumar, Vikash; Liu, Haiguang; Wu, Chun
• Is Part Of: Computers in biology and medicine. Volume 135(2021)
• Publication Date: 2021-08
• Subjects: SARS-CoV-2 -- Spike protein -- RBD -- Drug repurposing -- Virtual screening -- Molecular dynamics simulation -- Conformational ensemble; Medicine -- Data processing -- Periodicals; Biology -- Data processing -- Periodicals; 610.285
• DOI: 10.1016/j.compbiomed.2021.104634
• Languages: English
• ISSNs: 0010-4825

Abstract

Abstract: Severe 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. Graphical abstract: Image 1 Highlights: RBD of SARS-CoV-2 spike protein shows Conformational plasticity in long MD simulation. Top 18 drugs have good docking scores to bind with RBD at the ACE2-RBD interface. 16 out of the 18 drugs are obtained from the 3 MD conformations. 6 drugs exhibit stable binding with RBD at the ACE2-RBD interface in MD simulation. Gonadorelin, fondaparinux, atorvastatin and FAD are good anti-COVID-19 candidates.