title: Molecular modeling studies on benzimidazole carboxamide derivatives as PARP-1 inhibitors using 3D-QSAR and docking.
abstract: 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.
authors.affiliation: Key Laboratory of radiopharmaceuticals of Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
authors.forename: Huahui
authors.initials: H
authors.lastname: Zeng
authors.forename: Huabei
authors.initials: H
authors.lastname: Zhang
authors.forename: Fubin
authors.initials: F
authors.lastname: Jang
authors.forename: Lingzhou
authors.initials: L
authors.lastname: Zhao
authors.forename: Jianyuan
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000577:Amides; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C031000:benzimidazole; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases