Structural insight into PRMT5 inhibitors through amalgamating pharmacophore-based virtual screening, ADME toxicity, and binding energy studies to identify new inhibitors by molecular docking

Abstract

Protein arginine methyltransferase 5 (PRMT5) is a member of the methyltransferases family, a type II arginine enzyme that is crucial for many cellular processes and is associated with many cancer diseases. In this study, pharmacophore-based 3D QSAR modeling, virtual screening and binding free energy studies were carried out from a set of 61 potent compounds reported being inhibitors of PRMT5 protein. A vepoint pharmacophore model (AADHR) was generated and this model is used to generate an atom-based 3-Dimensional quantitative structure-activity relationship (3D-QSAR). The obtained 3D-QSAR model has high correlation coe cient (R 2 = 0.91), cross-validation coe cient (Q 2 = 0.82), F value (140.3), low RMSE (0.47) and pearson R-value (0.91). A library of 329825 molecules (ChEMBL database) is screened with pharmacophore model to retrieve hit molecules that are further subjected for molecular docking to identify best t-active conformations binding at the receptor site of PRMT5 protein. Further, we are calculated ADME and toxicity properties using QikProp module and pkCSM server and nally prioritized the lead molecules by binding free energy prediction.