Poly(ADP-ribose) polymerase (PARP)-based pharmacophore model development and its application in designing antitumor inhibitors

Abstract In this study, we suggest a workflow for the identification of potential leads targeted against poly(ADP-ribose) polymerase (PARP). To clarify the essential structure–activity relationship for the PARP inhibitors as well as identify potent leads against PARP, a qualitative pharmacophore model were established using a structure-based approach. The compounds in the Specs database were progressively filtered by the pharmacophore mapping, the rule of five, the molecular docking scores and the interactions with the critical active-site residues. The generated pharmacophore model consists of one hydrogen-bond acceptor feature, two hydrophobic features and the excluded volumes. It was validated using an internal database with a goodness of hit score of 0.87, and then utilized to screen the Specs database. Finally, nine structurally diverse compounds that showed better docking scores and the stronger interactions with the key amino acids were selected for further in vitro cytotoxicity assays. Biological evaluation indicated that all hits were found to be active with different degrees of inhibition at 40 μmol/L compound concentration. Compounds 2 (an IC 50 value of 22 μM) and 4 (an IC 50 value of 16 μM) exhibited moderate antiproliferative activities against MDA-MB-231 cancer cell line.