Prioritizing potential ACE2 inhibitors in the COVID-19 pandemic: Insights from a molecular mechanics-assisted structure-based virtual screening experiment

Abstract

Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound zinc metallopeptidase that generates the vasodilatory peptide angiotensin 1–7 and thus performs a protective role in heart disease. It is considered an important therapeutic target in controlling the COVID-19 outbreak, since SARS-CoV-2 enters permissive cells via an ACE2-mediated mechanism. The present in silico study attempted to repurpose existing drugs for use as prospective viral-entry inhibitors targeting human ACE2. Initially, a clinically approved drug library of 7,173 ligands was screened against the receptor using molecular docking, followed by energy minimization and rescoring of docked ligands. Finally, potential binders were inspected to ensure molecules with different scaffolds were engaged in favorable contacts with both the metal cofactor and the critical residues lining the receptor’s active site. The results of the calculations suggest that lividomycin, burixafor, quisinostat, fluprofylline, pemetrexed, spirofylline, edotecarin, and diniprofylline emerge as promising repositionable drug candidates for stabilizing the closed (substrate/inhibitor-bound) conformation of ACE2, thereby shifting the relative positions of the receptor’s critical exterior residues recognized by SARS-CoV-2. This study is among the rare ones in the relevant scientific literature to search for potential ACE2 inhibitors. In practical terms, the drugs, unmodified as they are, may be introduced into the therapeutic armamentarium of the ongoing fight against COVID-19 now, or their scaffolds may serve as rich skeletons for designing novel ACE2 inhibitors in the near future.

Peptide and peptide-based inhibitors of SARS-CoV-2 entry

“…The SARS-CoV-2 receptor ACE2 is an important factor in the renin-angiotensin system, where interference might have deleterious consequences. Indeed, the development of the ACE2 inhibitor MLN-4760 was stopped due to toxicity concerns after phase Ib/IIa clinical trials [ 80 , 81 ].…”

How glycobiology can help us treat and beat the COVID-19 pandemic

“…A new advanced in silico drug discovery method for novel coronavirus (SARS-CoV-2) with tensor decomposition-based unsupervised feature extraction described Gentamicin aminoglycoside antibiotic as candidate drug ( 84 ). Insights from a molecular mechanics-assisted structure-based virtual screening experiment showed Lividomycin aminoglycoside antibiotic as a potential ACE2 inhibitor in the COVID-19 pandemic ( 85 ) ( Table 1 and Figure 5 ). Besides their predicted binding to important proteins for SARS-CoV-2 infection, the aminoglycoside antibiotics are also translational inhibitors and defensin releasers that mediate antiviral activity as immunity enhancers ( 86 ), supporting their relevance for COVID-19 therapy.…”

A Bioelectromagnetic Proposal Approaching the Complex Challenges of COVID-19

“…What would be the medical intervention? The first logical deterministic answer is relatively straightforward: block the most probable "gate" of the ACE2 receiver [106]. Consequently, the application of the anti-ACE2 antagonist seems an optimal medication.…”