Background and ObjectiveThe current coronavirus disease-2019 (COVID-19) pandemic has triggered a worldwide health and economic crisis. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes the disease and completes its life cycle using the RNA-dependent RNA-polymerase (RdRp) enzyme, a prominent target for antivirals. In this study, we have computationally screened ∼690 million compounds from the ZINC20 database and 11,698 small molecule inhibitors from DrugBank to find existing and novel non-nucleoside inhibitors for SARS-CoV-2 RdRp. MethodsHerein, a combination of the structure-based pharmacophore modeling and hybrid virtual screening methods, including per-residue energy decomposition-based pharmacophore screening, molecular docking, pharmacokinetics, and toxicity evaluation were employed to retrieve novel as well as existing RdRp non-nucleoside inhibitors from large chemical databases. Besides, molecular dynamics simulation and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) method were used to investigate the binding stability and calculate the binding free energy of RdRp–inhibitor complexes. ResultsBased on docking scores and significant binding interactions with crucial residues (Lys553, Arg557, Lys623, Cys815, and Ser816) in the RNA binding site of RdRp, three existing drugs, ZINC285540154, ZINC98208626, ZINC28467879, and five compounds from ZINC20 (ZINC739681614, ZINC1166211307, ZINC611516532, ZINC1602963057, and ZINC1398350200) were selected, and the conformational stability of RdRp due to their binding was confirmed through molecular dynamics simulation. The free energy calculations revealed these compounds possess strong binding affinities for RdRp. In addition, these novel inhibitors exhibited drug-like features, good absorption, distribution, metabolism, and excretion profile and were found to be non-toxic. ConclusionThe compounds identified in the study by multifold computational strategy can be validated in vitro as potential non-nucleoside inhibitors of SARS-CoV-2 RdRp and holds promise for the discovery of novel drugs against COVID-19 in future.