Study summary · research use only
Drug repurposing against SARS-CoV-2 receptor binding domain using ensemble-based virtual screening and molecular dynamics simulations
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This computational study (no animal or human subjects) used ensemble-based virtual screening and molecular dynamics (MD) simulations to search for FDA-approved drugs that might bind the receptor binding domain (RBD) of the SARS-CoV-2 spike protein at its interface with ACE2. Researchers simulated RBD conformations and used them, plus the original crystal structure, to screen 2466 FDA-approved drugs, identifying 18 with top docking scores; 16 of these 18 came from the simulated conformations rather than the crystal structure. Further MD simulations of binding stability found 6 of the 18 drugs showed stable binding, with 3, gonadorelin, fondaparinux, and atorvastatin, showing enhanced binding after simulation. The authors state this approach may help identify agents that could block the ACE2-RBD interaction the virus uses to infect cells.
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.
pepmg summarizes the peer-reviewed literature and links to every source — it sells nothing, ships nothing, and gives no medical, dosing, or human-use guidance. Don't just trust this summary: follow the citation to its source and read it yourself. Research use only.