For coronaviruses, RNA-dependent RNA polymerase (RdRp) is an essential enzyme that catalyses the replication from RNA template and therefore remains an attractive therapeutic target for anti-COVID drug discovery. In the present study, we performed a comprehensive in silico screening for 16,776 potential molecules from recently established drug libraries based on two important pharmacophores (3-amino-4-phenylbutan-2-ol and piperazine). Based on initial assessment, 4042 molecules were obtained suitable as drug candidates, which were following Lipinski's rule. Molecular docking implemented for the analysis of molecular interactions narrowed this number of compounds down to 19. Subsequent to screening filtering criteria and considering the critical parameters viz. docking score and MM-GBSA binding free energy, 1-(4-((2S,3S)-3-amino-2-hydroxy-4-phenylbutyl)piperazin-1-yl)-3-phenylurea (compound 1) was accomplished to score highest in comparison to the remaining 18 shortlisted drug candidates. Notably, compound 1 displayed higher docking score (-8.069 kcal/mol) and MM-GBSA binding free energy (-49.56 kcal/mol) than the control drug, remdesivir triphosphate, the active form of remdesivir as well as adenosine triphosphate. Furthermore, a molecular dynamics simulation was carried out (100 ns), which substantiated the candidacy of compound 1 as better inhibitor. Overall, our systematic in silico study predicts the potential of compound 1 to exhibit a more favourable specific activity than remdesivir triphosphate. Hence, we suggest compound 1 as a novel potential drug candidate, which should be considered for further exploration and validation of its potential against SARS-CoV-2 in wet lab experimental studies.Communicated by Ramasawamy H. Sarma.

Amity Institute of Molecular Medicine and Stem Cell Research Amity University Uttar Pradesh Noida India

Department of Biology College of Arts and Sciences Georgia State University Atlanta GA USA

Department of Chemistry Miranda House University of Delhi Delhi India

Department of Health Research Ministry of Health and Family Welfare Government of India New Delhi India

Department of Medicinal Chemistry Key Laboratory of Chemical Biology School of Pharmaceutical Sciences Cheeloo College of Medicine Shandong University Jinan Shandong PR China

Department of Organic and Bioorganic Chemistry State Scientific Institution 'Institute for Single Crystals' of National Academy of Science of Ukraine Kharkiv Ukraine

Drug Discovery and Evaluation Unit Department of Parasitology Faculty of Science Charles University BIOCEV Vestec Czech Republic

Infection Biology Group Indian Foundation for Fundamental Research Rae Bareli India

Laboratory for Translational Chemistry and Drug Discovery Department of Chemistry Hansraj College University of Delhi Delhi India

Translational Health Science and Technology Institute Haryana India

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