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

Protein arginine methyltransferase 5 (PRMT5) is a member of the methyltransferases family, a type-II arginine enzyme crucial for many cellular processes and associated with many cancer diseases. In this study, 2D QSAR study, pharmacophore-based 3D QSAR modeling, virtual screening, and binding free energy studies were carried out from a set of 61 reported potent compounds being inhibitors of PRMT5 protein. A five-point 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 better correlation coefficient ( R 2 = 0.91), cross-validation coefficient ( Q 2 = 0.82), F value (140.3), low RMSE (0.47), and Pearson R value (0.91). A library of 329,825 molecules (ChEMBL database) is screened with the pharmacophore model to retrieve hit molecules that are further subjected for molecular docking to identify best fit-active conformations binding at the receptor site of PRMT5 protein. Furthermore, we calculated ADME and toxicity properties using the QikProp module and pkCSM server. The lead molecules were prioritized by glide scores and binding free energy studies. Finally, we have evaluated the stability of protein–ligand complexes by performing an all-atom MD simulation in explicit solvent. MD results further strengthen our findings.