Modulating Functional Allostery of Host-cell Receptor Protein hACE2 to Inhibit Viral Entry of SARS-CoV-2

Abstract

The emergence of new SARS-CoV-2 omicron sub-variants with a faster transmission rate has necessitated accelerated scientific explorations to confront another possible health emergency. The common anti-CoV therapeutic strategy targeting viral proteins proves inefficient in tackling virus evolutions due to mutations. Thus, the conserved host cell receptor angiotensin-converting enzyme 2 (hACE2) as a target, which paves the way for virus entry via interacting with the viral S protein's receptor binding domain (RBD), might be a rationale therapeutic strategy to curb all viral entry. However, this mandates searching for unknown non-orthosteric sites of hACE2 and its suitable binders (modulators), elucidating therapeutic efficacy with molecular insights, variant-specific effects, and retention of hACE2's natural function to avoid adversaries. Employing blind docking and unbiased molecular dynamics (MD) simulations, we discover a novel allosteric site of hACE2 far from its peptidase domain (PD). Exhaustive simulations demonstrate an allosteric modulator not only inhibits hACE2-RBD interaction by perturbing the spike RBD of SARS-CoV-2 but also bolsters hACE2's binding with its natural octapeptide substrate angiotensin II (AngII). Pharmacophore modeling and high-throughput virtual screening (HTVS) of large databases emanate more effectual modulators. Allosteric binders could downregulate hACE2's interaction with the RBD of three COVID-19 variants of concern (VOC): beta, delta, and omicron. Dynamic residual network analysis discerns the shortest suboptimal pathway through which the allostery signal gets transmitted from the allosteric site to the RBD. We hail the proposed allosteric site and mechanistic details for developing more powerful therapeutic options against SARS-CoV-2 variants.