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Benzimidazole compound abrogates SARS-COV-2 receptor-binding domain (RBD)/ACE2 interaction In vitro.
Omotuyi, Olaposi; Olatunji, Olusina M; Nash, Oyekanmi; Oyinloye, Babatunji; Soremekun, Opeyemi; Ijagbuji, Ayodeji; Fatumo, Segun.
  • Omotuyi O; Institute for Drug Research and Development, S.E. Bogoro Center, Afe Babalola University, Ado-Ekiti, Nigeria; Department of Pharmacology and Toxicology, College of Pharmacy, Afe Babalola University, Ado-Ekiti, Nigeria; Bio-Computing & Drug Research Unit, Mols and Sims, Ado Ekiti, Ekiti State, Ni
  • Olatunji OM; Department of Pharmacology and Toxicology, College of Pharmacy, Afe Babalola University, Ado-Ekiti, Nigeria.
  • Nash O; Center for Genomics Research and Innovation, National Biotechnology Development Agency, Abuja, PMB 5118, Nigeria.
  • Oyinloye B; Institute for Drug Research and Development, S.E. Bogoro Center, Afe Babalola University, Ado-Ekiti, Nigeria; Phytomedicine, Biochemical Toxicology and Biotechnology Research Laboratories, Department of Biochemistry, College of Sciences, Afe Babalola University, PMB 5454, Ado-Ekiti, 360001, Nigeria;
  • Soremekun O; The African Computational Genomics (TACG) Research Group, MRC/UVRI, and LSHTM, Entebbe, Uganda.
  • Ijagbuji A; Pharmaceutics International, Inc. Hunt Valley, Maryland, United States.
  • Fatumo S; The African Computational Genomics (TACG) Research Group, MRC/UVRI, and LSHTM, Entebbe, Uganda; H3Africa Bioinformatics Network (H3ABioNet) Node, Centre for Genomics Research and Innovation, NABDA/FMST, Abuja, Nigeria; Department of Non-Communicable Disease Epidemiology, London School of Hygiene and
Microb Pathog ; 176: 105994, 2023 Mar.
Article in English | MEDLINE | ID: covidwho-2181626
ABSTRACT
The development of clinically actionable pharmaceuticals against coronavirus disease (COVID-19); an infectious disease caused by the SARS-CoV-2 virus is very important for ending the pandemic. Coronavirus spike glycoprotein (GP)-Receptor Binding Domain (RBD) and its interaction with host receptor angiotensin converting enzyme 2 (ACE2) is one of the most structurally understood but therapeutically untapped aspect of COVID-19 pathogenesis. Binding interface based on previous x-ray structure of RBD/ACE2 were virtually screened to identify fragments with high-binding score from 12,000 chemical building blocks. The hit compound was subjected to fingerprint-based similarity search to identify compounds within the FDA-approved drug library containing the same core scaffold. Identified compounds were then re-docked into of RBD/ACE2. The best ranked compound was validated for RBD/ACE2 inhibition using commercial kit. Molecular dynamics simulation was conducted to provide further insight into the mechanism of inhibition. From the original 12000 chemical building blocks, benzimidazole (BAZ) scaffold was identified. Fingerprint-based similarity search of the FDA-approved drug library for BAZ-containing compounds identified 12 drugs with the benzimidazole-like substructure. When these compounds were re-docked into GP/ACE2 interface, the consensus docking identified bazedoxifene as the hit. In vitro RBD/ACE2 inhibition kinetics showed micromolar IC50 value (1.237 µM) in the presence of bazedoxifene. Molecular dynamics simulation of RBD/ACE2 in the presence BAZ resulted in loss of contact and specific hydrogen-bond interaction required for RBD/ACE2 stability. Taken together, these findings identified benzimidazole scaffold as a building block for developing novel RBD/ACE2 complex inhibitor and provided mechanistic basis for the use of bazedoxifene as a repurposable drug for the treatment of COVID-19 acting at RBD/ACE2 interface.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Type of study: Prognostic study Limits: Humans Language: English Journal: Microb Pathog Journal subject: Communicable Diseases / Microbiology Year: 2023 Document Type: Article Affiliation country: J.micpath.2023.105994

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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Type of study: Prognostic study Limits: Humans Language: English Journal: Microb Pathog Journal subject: Communicable Diseases / Microbiology Year: 2023 Document Type: Article Affiliation country: J.micpath.2023.105994