Targeting the RBD of Omicron Variant (B.1.1.529) with Medicinal Phytocompounds to Abrogate the Binding of Spike Glycoprotein with the hACE2 Using Computational Molecular Search and Simulation Approach

SIMPLE SUMMARY: The current study based on virtual drugs screening and simulations identified novel drugs to target the RBD of the spike protein from Omicron variant of SARS-CoV-2. Using molecular modeling tools to search for a good binding drugs we identified SANC00944, SANC01032, SANC00992, and SANC00317 from South African natural compounds database as potential inhibitor of the Spike-ACE2 complex. In sum, this study will help in the design and discovery of novel drug therapeutics, which may be used against the emerging Omicron variant of SARS-CoV-2. ABSTRACT: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus continues to inflict chaos globally. The emergence of a novel Omicron variant (B.1.1.529) in South Africa harbors 30 mutations in the spike protein. The variant is distinguished from other variants of concern (VOCs) with an increased (15) number of mutations in the receptor-binding domain (RBD) and suggests higher chances of causing reinfections. Initial reports also claimed that this variant escapes all the neutralizing antibodies, thus demanding a novel strategy against it. Thus, in this study, we performed a computational molecular screening against the RBD of the Omicron (B.1.1.529) variant and assessed the binding affinity of potent drugs against the RBD. The multi-steps screening of the South African Natural Compounds Database (SANCDB) revealed four medicinal compounds as excellent (potential) anti-viral agents against the Omicron variant, namely SANC00944, SANC01032, SANC00992, and SANC00317. The simulation analysis of these compounds in complex with the RBD demonstrated stable dynamics and structural compactness. Moreover, the residual flexibility analysis revealed that the flexibility of three loops required for interaction with hACE2 has been reduced by the binding of these drugs. The post-simulation validation of these compounds such as binding free energy, in silico bioactivity, and dissociation constant prediction validated the anti-viral potency of these compounds. The total binding free energy (TBFE) for the SANC01032–RBD complex was reported to be −46.54 kcal/mol; for the SANC01032–RBD complex, the TBFE was −41.88 kcal/mol; for the SANC00992–RBD complex the TBFE was −29.05 kcal/mol, while for the SANC00317–RBD complex the TBFE was −31.03 kcal/mol. The results showed the inhibition potential of these compounds by targeting the RBD. In conclusion, this study will help in the design and discovery of novel drug therapeutics, which may be used against the emerging Omicron variant of SARS-CoV-2.