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Prioritizing potential ACE2 inhibitors in the COVID-19 pandemic: Insights from a molecular mechanics-assisted structure-based virtual screening experiment.
Terali, Kerem; Baddal, Buket; Gülcan, Hayrettin Ozan.
  • Terali K; Department of Medical Biochemistry, Near East University, Nicosia, 99138, Cyprus; Bioinformatics & Computational Biology Research Group, DESAM Institute, Near East University, Nicosia, 99138, Cyprus. Electronic address: kerem.terali@neu.edu.tr.
  • Baddal B; Department of Medical Microbiology and Clinical Microbiology, Near East University, Nicosia, 99138, Cyprus; Microbial Pathogenesis Research Group, DESAM Institute, Near East University, Nicosia, 99138, Cyprus.
  • Gülcan HO; Department of Pharmaceutical Chemistry, Eastern Mediterranean University, Famagusta, 99628, Cyprus.
J Mol Graph Model ; 100: 107697, 2020 11.
Article in English | MEDLINE | ID: covidwho-665694
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Angiotensin-Converting Enzyme Inhibitors / Peptidyl-Dipeptidase A / Small Molecule Libraries / Betacoronavirus Type of study: Observational study / Prognostic study Limits: Humans Language: English Journal: J Mol Graph Model Journal subject: Molecular Biology Year: 2020 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Angiotensin-Converting Enzyme Inhibitors / Peptidyl-Dipeptidase A / Small Molecule Libraries / Betacoronavirus Type of study: Observational study / Prognostic study Limits: Humans Language: English Journal: J Mol Graph Model Journal subject: Molecular Biology Year: 2020 Document Type: Article