Repurposing benzimidazole and benzothiazole derivatives as potential inhibitors of SARS-CoV-2: DFT, QSAR, molecular docking, molecular dynamics simulation, and in-silico pharmacokinetic and toxicity studies

Ranjan K Mohapatra; Kuldeep Dhama; Amr Ahmed El-Arabey; Ashish K Sarangi; Ruchi Tiwari; Talha Bin Emran; Mohammad Azam; Saud I Al-Resayes; Mukesh K Raval; Veronique Seidel; Mohnad Abdalla

doi:10.1016/j.jksus.2021.101637

Repurposing benzimidazole and benzothiazole derivatives as potential inhibitors of SARS-CoV-2: DFT, QSAR, molecular docking, molecular dynamics simulation, and in-silico pharmacokinetic and toxicity studies

J King Saud Univ Sci. 2021 Dec;33(8):101637. doi: 10.1016/j.jksus.2021.101637. Epub 2021 Oct 7.

Authors

Affiliations

¹ Department of Chemistry, Government College of Engineering, Keonjhar, Odisha 758002, India.
² Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, Uttar Pradesh, India.
³ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
⁴ Department of Chemistry, School of Applied Sciences, Centurion University of Technology and Management, Odisha, India.
⁵ Department of Veterinary Microbiology and Immunology, College of Veterinary Sciences, Uttar Pradesh Pandit Deen Dayal Upadhyaya Pashu Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sansthan (DUVASU), Mathura 281001, India.
⁶ Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh.
⁷ Department of Chemistry, College of Science, King Saud University, PO BOX 2455, Riyadh 11451, Saudi Arabia.
⁸ Department of Chemistry, G. M. University, Sambalpur, Odisha, India.
⁹ Natural Products Research Laboratory, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, United Kingdom.
¹⁰ Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Cultural West Road, Shandong Province 250012, PR China.

Abstract

Density Functional Theory (DFT) and Quantitative Structure-Activity Relationship (QSAR) studies were performed on four benzimidazoles (compounds 1-4) and two benzothiazoles (compounds 5 and 6), previously synthesized by our group. The compounds were also investigated for their binding affinity and interactions with the SARS-CoV-2 M^pro (PDB ID: 6LU7) and the human angiotensin-converting enzyme 2 (ACE2) receptor (PDB ID: 6 M18) using a molecular docking approach. Compounds 1, 2, and 3 were found to bind with equal affinity to both targets. Compound 1 showed the highest predictive docking scores, and was further subjected to molecular dynamics (MD) simulation to explain protein stability, ligand properties, and protein-ligand interactions. All compounds were assessed for their structural, physico-chemical, pharmacokinetic, and toxicological properties. Our results suggest that the investigated compounds are potential new drug leads to target SARS-CoV-2.

Keywords: ACE2; DFT; MD simulation; Molecular docking; Pharmacokinetic study; QSAR; SARS-CoV-2 Mpro.