Computational Study of Substituted 5[H] - Phenanthradin-6-Ones as Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors by Analog and Structure Based Methods

Abstract

The poly (ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear protein involved in DNA repair and programmed cell death. Substituted 5(H) phenanthradin-6-one analogs were found to be potent PARP-1 inhibitors. Semiempirical methods were used to estimate various physicochemical parameters. The hydration energy (HE), ionization potential (IP), electrophilic index (ω) and partition coefficient ( LogP ) were resulted as independent variables for inhibitory activity of the analogs. The overall increase of HE, IP, and EI and overall decrease of LogP enhance the efficacy of inhibitory nature of these analogs to PARP-1. Docking studies of 5(H) phenanthradin-6-one analogs with PARP-1 were also performed in support of the findings of QSAR studies. Analysis of results of both QSAR and docking studies suggested that remarkable inhibitory activity is exhibited by molecules 9b, 10b1 and 10b2. The hydrogen bond interactions along with hydrophobic and electrostatic interactions are mapped to confirm their potencies.