Molecular Modeling Studies on Benzimidazole Carboxamide Derivatives as PARP-1 Inhibitors Using 3D-QSAR and Docking

作者：Zeng, Huahui; Zhang, Huabei^*; Jang, Fubin; Zhao, Lingzhou; Zhang, Jianyuan

来源：Chemical Biology & Drug Design, 2011, 78(3): 333-352.

DOI：10.1111/j.1747-0285.2011.01139.x

• 3D-QSAR
• CoMFA
• CoMSIA
• docking
• poly(ADP-ribose) polymerases

Poly(ADP-ribose) polymerases (PARPs) play significant roles in various cellular functions including DNA repair and control of RNA transcription. PARP-1 inhibitors have been demonstrated to potentiate the effect of cytotoxic agents or radiation in a number of animal tumor models. To understand the structure-activity correlation of cyclic amine-containing benzimidazole carboxamide-based PARP-1 inhibitors, we have carried out a combined molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling study. Two types of satisfactory substructure-based 3D-QSAR models were built, including the comparative molecular field analysis (CoMFA) model (r(2), 0.913; q(2), 0.743) and comparative molecular similarity indices analysis (CoMSIA) model (r(2), 0.869; q(2), 0.734), to predict the biologic activity of new compounds. Docking studies were performed to explore the binding mode between all of the inhibitors and the PARP-1 and produce the bioactive conformation of each compound in the whole data set. The docked conformer-based alignment strategy gave the best 3D-QSAR models, CoMFA model (r(2), 0.899; q(2), 0.712) and CoMSIA model (r(2), 0.889; q(2), 0.744), respectively. The structural insights obtained from both the 3D-QSAR contour maps and molecular docking help to better interpret the structure-activity relationship. The information obtained from molecular modeling studies helped us to predict the activity of new inhibitors and further design some novel and potent PARP-1 enzyme inhibitors.

• 出版日期2011-9
• 单位北京师范大学