Blocking key mutated hotspot residues in the RBD of the omicron variant (B.1.1.529) with medicinal compounds to disrupt the RBD-hACE2 complex using molecular screening and simulation approaches

Abstract

A new variant of SARS-CoV-2 known as the omicron variant (B.1.1.529) reported in South Africa with 30 mutations in the whole spike protein, among which 15 mutations are in the receptor-binding domain, is continuously spreading exponentially around the world.

Computational modeling of the effect of five mutations on the structure of the ACE2 receptor and their correlation with infectivity and virulence of some emerged variants of SARS-CoV-2 suggests mechanisms of binding affinity dysregulation

“…The mutant residue R493 maintains these interactions and additionally forms new interactions with residues D30 and D38 of ACE2 WT ( Supplementary Table S2 ). These new interactions could impact the binding affinity between ACE2-RBD-S, and according to Khan A et al [ 59 ], Q493R mutation leads to more stable interactions with the ACE2 protein. Additionally, in previous studies, it has been shown that Q493R in the RBD spike is significantly associated with Omicron disease severity in patients.…”

Ultra-Large-Scale Screening of Natural Compounds and Free Energy Calculations Revealed Potential Inhibitors for the Receptor-Binding Domain (RBD) of SARS-CoV-2

“…These computational methods have been previously used to design potential inhibitors for SARS-CoV-2. For instance, molecular modelling and simulation-based approaches have been used to target the RBD of the Omicron variant [ 13 ]. Similarly, drug repurposing and molecular screening-based approaches also identified potential small molecules for other proteins such as 3CLpro, PLpro, RdRp, S protein, and NRP1 [ 16 , 17 ].…”

“…Using structural modeling approaches, Abbas et. al reported that Tyr453, Arg493, Ser494, Ser496, Tyr501, and His505 are essential residues targeted by the shortlisted compounds and consequently abrogate the RBD-ACE2 complex in the case of the Omicron variant (B.1.1.529) [ 13 ]. Moreover, the role of Arg403, Asn417, Tyr501, and His505 in the higher infectivity of other variants has also been revealed, thus showing promising results for the inhibition of the PPI complex [ 18 ].…”

“…Keeping in mind the importance of the SARS-CoV-2 RBD of the spike protein as an effective drug target, we used the virtual screening of an ultra-large drug library and experimental approaches to identify a small molecule. In previous studies, 3CLpro, PLpro, the RBD, RdRp, and other druggable proteins were targeted by using molecular screening approaches to control the viral spread [ 13 , 14 , 15 ]. The top hits were re-evaluated and validated by using molecular simulation-based approaches.…”

SARS-CoV-2 VOCs, Mutational diversity and clinical outcome: Are they modulating drug efficacy by altered binding strength?

“…Furthermore, Shafiq et al demonstrated that one of the SARS-CoV-2 variants in Tanzania, the A.30 strain, manifesting the mutations R346K, T478K, and E484K in the Spike-RBD region, aids the virus with immune escape properties [ 51 ]. The Omicron variant, harbours a large number of mutations in the RBD region of the spike protein, including K417N, G446S, Q493R, and Q498R, leading to more stable interactions with the hACE2 protein [ 23 ]. Hence, these hotspot mutations in the Omicron have been considered as a potential target for drug design and repurposing to combat the viral spread [ 24 ].…”