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

Autor: Banerjee S; Department of Physical Sciences, University of Arkansas Fort Smith, 5210 Grand Avenue, Fort Smith, Arkansas 72904, United States., Yadav S; Department of Chemistry, Shiv Nadar University, Gautam Buddha Nagar, Uttar Pradesh 201314, India., Banerjee S; Department of Chemistry, School of Basic and Applied Sciences, Adamas University, Kolkata 700126, India., Fakayode SO; Department of Physical Sciences, University of Arkansas Fort Smith, 5210 Grand Avenue, Fort Smith, Arkansas 72904, United States., Parvathareddy J; Regional Biocontainment Laboratory, University of Tennessee Health Science Center, 901 Monroe Avenue, Memphis, Tennessee 38163, United States., Reichard W; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Surendranathan S; Regional Biocontainment Laboratory, University of Tennessee Health Science Center, 901 Monroe Avenue, Memphis, Tennessee 38163, United States., Mahmud F; Department of Bioengineering, Rice University, 6100 Main Street, Houston, Texas 77005, United States., Whatcott R; Department of Physical Sciences, University of Arkansas Fort Smith, 5210 Grand Avenue, Fort Smith, Arkansas 72904, United States., Thammathong J; Department of Physical Sciences, University of Arkansas Fort Smith, 5210 Grand Avenue, Fort Smith, Arkansas 72904, United States., Meibohm B; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Miller DD; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Jonsson CB; Regional Biocontainment Laboratory, University of Tennessee Health Science Center, 901 Monroe Avenue, Memphis, Tennessee 38163, United States.; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Dubey KD; Department of Chemistry, Shiv Nadar University, Gautam Buddha Nagar, Uttar Pradesh 201314, India.
Jazyk: angličtina
Zdroj: Journal of chemical information and modeling [J Chem Inf Model] 2021 Nov 22; Vol. 61 (11), pp. 5469-5483. Date of Electronic Publication: 2021 Oct 20.
DOI: 10.1021/acs.jcim.1c00524
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz: