Drug Repurposing to Identify Nilotinib as a Potential SARS-CoV-2 Main Protease Inhibitor: Insights from a Computational and In Vitro Study

Abstract

COVID-19, an acute viral pneumonia, has emerged as a devastating pandemic. Drug repurposing allows researchers to find different indications of FDA-approved or investigational drugs. In this current study, a sequence of pharmacophore and molecular modeling-based screening against COVID-19 M pro (PDB: 6LU7) suggested a subset of drugs, from the Drug Bank database, which may have antiviral activity. A total of 44 out of 8823 of the most promising virtual hits from the Drug Bank were subjected to molecular dynamics simulation experiments to explore the strength of their interactions with the SARS-CoV-2 M pro active site. MD findings point toward three drugs (DB04020, DB12411, and DB11779) with very low relative free energies for SARS-CoV-2 M pro with interactions at His41 and Met49. MD simulations identified an additional interaction with Glu166, which enhanced the binding affinity significantly. Therefore, Glu166 could be an interesting target for structure-based drug design. Quantitative structural–activity relationship analysis was performed on the 44 most promising hits from molecular docking-based virtual screening. Partial least square regression accurately predicted the values of independent drug candidates’ binding energy with impressively high accuracy. Finally, the EC 50 and CC 50 of 10 drug candidates were measured against SARS-CoV-2 in cell culture. Nilotinib and bemcentinib had EC 50 values of 2.6 and 1.1 μM, respectively. In summary, the results of our computer-aided drug design provide a roadmap for rational drug design of M pro inhibitors and the discovery of certified medications as COVID-19 antiviral therapeutics.

In silico exploration of disulfide derivatives of Ferula foetida oleo-gum (Covexir®) as promising therapeutics against SARS-CoV-2

“…The MM-GBSA method using molecular mechanics (MM), the Generalized Born (GB) electrostatics, and solvent accessibility (SA) models estimate the binding energy. This method is a reliable and efficient model, which is widely utilized to calculate binding free energy binding free energies of noncovalently bound complexes [ 13 , [38] , [39] , [40] ] Here, the gmx_MMPBSA python script is used for compute binding free energy from the MD productions. The binding free energy for ligand-receptor complexes can be computed as follows: where the , , and are the Gibbs free energy of ligand-receptor complex, receptor, and ligand, respectively.…”

A Computer-Aided Approach for the Discovery of D-Peptides as Inhibitors of SARS-CoV-2 Main Protease

“…Structure-based virtual screening (SBVS) of diverse ligand databases, many of them containing drug repurposing candidates and natural products, has been extensively applied to identify potential 3CL pro inhibitors (Wu C. et al, 2020;Chowdhury et al, 2020;Jukic et al, 2020;Meyer-Almes, 2020;Olubiyi et al, 2020;Selvaraj et al, 2020;Federico et al, 2021;Gogoi et al, 2021;Guedes et al, 2021;Kumar et al, 2021;Lokhande et al, 2021;Naik et al, 2021;Rajpoot et al, 2021;Rehman et al, 2021;Sisakht et al, 2021). In several cases, this approach has led to the successful identification of compounds displaying in vitro inhibitory activity against 3CL pro (Ghahremanpour et al, 2020;Gupta et al, 2020;Jin et al, 2020;Li et al, 2020;Alves et al, 2021;Banerjee et al, 2021;Gunther et al, 2021;Guo et al, 2021;Gupta et al, 2021;Hamdy et al, 2021;Pathak et al, 2021;Yang et al, 2021). On the other hand, protein-peptide docking remains far more challenging compared to other small molecules due to the higher flexibility of peptides (Rentzsch and Renard, 2015;Ciemny et al, 2018;Hashemi et al, 2021).…”

Identification of clinical candidates against West Nile virus by activity screening in vitro and effect evaluation in vivo

“…Because of the long time in developing a novel antiviral drug, screening of clinically existing approved drugs may shorten the time of drug development for the treatment of an emerging virus infection and was widely used in recent years. Drug repurposing screens have led to discoveries of potential new candidate therapies for new merging or reemerging viruses, such as Ebola virus, 9 Middle East respiratory syndrome coronavirus, 10 Zika virus (ZIKV), 11 Lassa virus, 12 and respiratory syndrome coronavirus 2 (SARS‐CoV‐2) 13–15 . In this study, we screened clinical candidates for the treatment of WNV infection from 978 Food Drug Administration (FDA)‐approved small‐molecule drugs.…”

“…Drug repurposing screens have led to discoveries of potential new candidate therapies for new merging or reemerging viruses, such as Ebola virus, 9 Middle East respiratory syndrome coronavirus, 10 Zika virus (ZIKV), 11 Lassa virus, 12 and respiratory syndrome coronavirus 2 (SARS-CoV-2). [13][14][15] In this study, we screened clinical candidates for the treatment of WNV infection from 978 Food Drug Administration (FDA)-approved small-molecule drugs. Four compounds, including cilnidipine, mycophenolate mofetil, nitazoxanide, and teriflunomide, were found to have high inhibition activity for WNV with low cytotoxicity.…”