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The outbreak of SARS-CoV-2 infections around the world has prompted scientists to explore different approaches to develop therapeutics against COVID-19. This study focused on investigating the mechanism of inhibition of clioquinol (CLQ) and its derivatives (7-bromo-5-chloro-8-hydroxyquinoline (CLBQ), 5, 7-Dichloro-8-hydroxyquinoline (CLCQ)) against the viral glycoprotein, and human angiotensin-converting enzyme-2 (hACE-2) involved in SARS-CoV-2 entry. The drugs were docked at the exopeptidase site of hACE-2 and receptor binding domain (RBD) sites of SARS-CoV-2 S gp  to calculate the binding affinity of the drugs. To understand and establish the inhibitory characteristics of the drugs, molecular dynamic (MD) simulation of the best fit docking complex performed. Evaluation of the binding energies of the drugs to hACE-2 after 100 ns MD simulations revealed CLQ to have the highest binding energy value of −40.4 kcal/mol close to MLN-7640 (-45.4 kcal/mol), and higher than the exhibited values for its derivatives: CLBQ (-34.5 kcal/mol) and CLCQ (-24.8 kcal/mol). This suggests that CLQ and CLBQ bind more strongly at the exopeptidase site than CLCQ. Nevertheless, the evaluation of binding affinity of the drugs to SARS-CoV-2 S gp  showed the drugs are weakly bound at the RBD site, with CLBQ, CLCQ, CLQ exhibiting relatively low energy values of −16.8 kcal/mol, −16.34 kcal/mol, −12.5 kcal/mol, respectively compared to the reference drug, Bisoxatin (BSX), with a value of −25.8 kcal/mol. The structural analysis further suggests decrease in systems stability and explain the mechanism of inhibition of clioquinol against SARS-CoV-2 as reported in previous  in vitro  study. Communicated by Ramaswamy H. Sarma

journal of biomolecular structure and dynamics

Inhibitory mechanism of clioquinol and its derivatives at the exopeptidase site of human angiotensin-converting enzyme-2 and receptor binding domain of SARS-CoV-2 viral spike