The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) outbreak is posing a serious public health threat worldwide in the form of COVD-19. Herein, we have performed two-dimensional quantitative structure-activity relationship (2D-QSAR) and three-dimensional pharmacophore modelling analysis employing inhibitors of 3-chymotrypsin-like protease (3CLpro), the leading protease that is crucial for the replication of SARS-CoV-2. The investigation aims to identify the important structural features responsible for the enzyme inhibition and the search for novel 3CLpro enzyme inhibitors as effective therapeutics for treating SARS-CoV-2. Furthermore, we carried out molecular docking studies using the most and least active compounds in the dataset, aiming to validate the contributions of various features as appeared in the QSAR models. Later, the stringently validated 2D-QSAR model was used to estimate the 3CLpro inhibitory activity of compounds from five chemical databases. Compounds with the significant predicted activity were then subjected to pharmacophore-based virtual screening to screen the top-rated compounds, which were then further subjected to molecular docking analysis, absorption, distribution, metabolism, excretion - toxicity (ADMET) profiling, and molecular dynamics (MD) simulation. The multi-step virtual screening analyses suggested that compounds CASAntiV-865453-58-3, CASAntiV-865453-40-3, and CASAntiV-2043031-84-9 could be used as effective therapeutic agents for the treatment of SARS-CoV-2.
Keywords: 2D-QSAR; 3CLpro; 3D-QSAR; ADMET; SARS CoV-2; docking.