Understanding structural characteristics of PARP-1 inhibitors through combined 3D-QSAR and molecular docking studies and discovery of new inhibitors by multistage virtual screening

Abstract

Poly(ADP-ribose) polymerase (PARP) belongs to family of nuclear proteins having a critical role in base excision DNA repair system by catalysing the process of poly(ADP-ribosyl)ation leading to cell proliferation. The role of PARP inhibitors as anticancer agents was accepted after the approval of olaparib for the treatment of BRCA mutation-induced ovarian cancer. A combined ligand-based and receptor-based approach has been reported here for identification of PARP-1 inhibitors. Seventy one analogues of phthalazinone and 4-carboxamide benzimidazole showing activities against PARP-1 were used to develop ligand-based pharmacophore hypothesis using PHASE. The five-point pharmacophore hypothesis ADHRR.1031 was developed, and atom-based 3D-QSAR studies were carried. The developed 3D QSAR model has good correlation coefficient value (R2 = 0.952) and cross validated with correlation coefficient value (Q2 = 0.764). To further ascertain the structural requirement for PARP-1 inhibition, molecular interaction studies of inhibitors with PARP-1 were carried out by performing docking studies using Glide 5.6. Hydrogen bond interaction with Gly202 and Ser243 is an important interaction observed by the carboxyl amide group. The pharmacophore model depicts the importance of the hydrogen bond donor and acceptor nature of the carboxyl amide group. Further multistage virtual screening was performed to screen molecules with possible PARP-1 inhibition. Initial screening was performed based on pharmacophoric features followed by docking that consisted of HTVS, SP, and XP docking and final optimisation by Prime MM-GBSA calculation. The screened molecules were further scrutinised for their ADME-toxicity properties.