Design and Molecular modeling of some phthalazinone derivatives as PARP2 Inhibitors

Abstract

Poly-ADP-ribose polymerases -2 (PARP-2) is an important nuclear enzyme involved in the detection and repair of DNA damage. Inhibition of PARP activity is very useful in cancer therapy. Olaparib also known as AZD2281 or KU-0059436 is a famous potent inhibitor of both PARP-1 and PARP-2, belongs to the class of phthalazinones, used as standard reference in this study. 65 compounds of phthalazinones derivatives were designed, all these compounds have a nicotinamide-based structure aimed at competing with NAD+ for the binding to PARP-2 catalytic site. ACD/Chemical Sketch Software was used to draw chemical structures, calculation of molecular properties and prediction of log P. 45 compounds which have chemical parameters values closes to the reference standard (Olaparib) were chosen to be docked into the inhibitor site of protein by using surflex software (syblyl). Among these derivatives seven compounds showed promising score higher than Olaparib. Docking data revealed that (4-[5-(2-amino-3-cyclopropyl-1,3-dihydroxypropyl)-2-flurobenzyl] phthalazine-1(2H)-one) was the top –ranked result in term of its binding to PARP-2 enzyme, with Surflex score of (-logkd=9.71). Docking results were used to predict molecular interactions; and molecular recognition pattern in PARP-2 inhibitor complexes, were analyzed by online discovery studio software.