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?:abstract
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AIM We seek to provide an understanding of the binding mechanism of Remdesivir, provide structural and conformational implications on SARS-CoV-2 virus RNA-dependent RNA polymerase upon its binding and identify its crucial pharmacophoric moieties. BACKGROUND The coronavirus disease of 2019 (COVID-19) pandemic has infected over a million people, with over 65,000 deaths as of the first quarter of 2020. The current limitation of effective treatment options with no approved vaccine or targeted therapeutics for the treatment of COVID-19 has posed serious global health threats. This has necessitated several drug and vaccine development efforts across the globe. To date, the farthest in the drug development pipeline so far is Remdesivir. OBJECTIVES We perform molecular dynamics simulation, quantify the energy contributions of binding site residues using per-residue energy decomposition calculations, and subsequently generate a pharmacophore model for the identification of potential SARS-CoV-2 virus RNA-dependent RNA polymerase inhibitors. METHODS Integrative molecular dynamics simulations and thermodynamic calculations coupled with advanced postmolecular dynamics analysis techniques were employed. RESULTS Our analysis showed that the modulatory activity of Remdesivir is characterized by an extensive array of highaffinity and consistent molecular interactions with specific active site residues that anchor Remdemsivir within the binding pocket for efficient binding. These residues are ASP452, THR456, ARG555, THR556, VAL557, ARG624, THR680, SER681, and SER682. Results also showed that Remdesivir binding, induces minimal individual amino acid perturbations, subtly interferes with deviations of C-α atoms and restricts the systematic transition of SARS-CoV-2 RNA-dependent RNA polymerase from the \'buried\' hydrophobic region to the \'surface-exposed\' hydrophilic region. We also mapped a pharmacophore model based on observed high-affinity interactions with SARS-CoV-2 virus RNA-dependent RNA polymerase, which showcased the crucial functional moieties of Remdesivir and was subsequently employed for virtual screening. CONCLUSION The structural insights and the optimized pharmacophoric model provided would augment the design of improved analogs of Remdesivir that could expand treatment options for COVID-19.
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