Computational insights into binding mechanism of drugs as potential inhibitors against SARS-CoV-2 targets

Because of the scale of the novel coronavirus (COVID-19) pandemic and the swift transmission of this highly contagious respiratory virus, repurposing existing drugs has become an urgent treatment approach. The objective of our study is to unravel the binding mechanism of the Food and Drug Administration (FDA)-approved dexamethasone (Dex) and boceprevir (Boc) drugs with selected COVID-19 protein targets SARS-CoV-2 spike protein C-terminal domain (spike-CTD), main protease (M(pro)), and interleukin-6 (IL-6). Another objective is to analyze the effects of binding Dex and Boc drugs on the interactions of viral spike protein to human angiotensin-converting enzyme 2 (hACE2). Molecular docking and one-microsecond-long molecular dynamics simulations of each of the six protein–drug complexes along with steered molecular dynamics (SMD) and umbrella sampling (US) methods have revealed the binding mode interactions and the physicochemical stability of the three targeted proteins with two drugs. Results have shown that both drugs bind strongly with the three protein targets through hydrogen bonding and hydrophobic interactions. A major finding from this study is how the binding of the drugs with viral spike protein affects its interactions at the binding interface with hACE2 protein. Simulations of drug-bound spike-CTD with hACE2 show that due to the presence of a drug at the binding interface of spike-CTD, hACE2 is being blocked from making putative interactions with viral protein at such interface. These important findings regarding the binding affinity and stability of the two FDA-approved drugs with the main targets of COVID-19 along with the effect of drugs on hACE2 interactions would contribute to COVID-19 drug discovery and development. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11696-021-01843-0.