Identification of lead small molecules for the design and development of potent severe acute respiratory syndrome coronavirus 2 main protease inhibitors

The repercussions of the COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are catastrophic, and the world has yet to achieve full recovery. Several inhibitors targeting SARS-CoV-2 main protease are experiencing diminished efficacy owing to resistance-inducing mutations. The current situation implies that the quest to find potent and resilient SARS-CoV-2 main protease drugs to overcome resistance must be a continuous effort. Here, multiple receptor virtual screening and molecular dynamics (MD) simulation techniques were employed to identify novel binders from an integrated small-molecule database as leads for the discovery, design, and development of antivirals immune to resistance by SARS-CoV-2 main protease. The small-molecule database was initially screened separately against five SARS-CoV-2 main protease structures with different substrate-binding site conformations using the GOLD program, after which the fitness score of a control compound was used as the cutoff to create a shortlist of potential hits in each case. Then, 21 compounds at the intersection of all five shortlists were selected as virtual screening hits. The hits were subjected to MD simulations, identifying four novel compounds capable of remaining bound to SARS-CoV-2 main protease for up to 100 ns. Analysis of the mode of binding and interactions between each of the four compounds and SARS-CoV-2 main protease revealed that the compounds fit better into the conserved subpockets of the substrate-binding site than the control and interact with important amino acid residues. Conjointly, MD simulations, binding energy, and toxicity analysis results further demonstrated that the compounds are promising leads for the discovery, design, and development of potent drugs to augment the fight against SARS-CoV-2 main protease resistance.