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Molecular modeling studies on benzimidazole carboxamide derivatives as PARP-1 inhibitors using 3D-QSAR and docking.
Chem Biol Drug Des. 2011 Sep; 78(3):333-52.CB

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+Show Affiliations

Key Laboratory of radiopharmaceuticals of Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21585709

Citation

Zeng, Huahui, et al. "Molecular Modeling Studies On Benzimidazole Carboxamide Derivatives as PARP-1 Inhibitors Using 3D-QSAR and Docking." Chemical Biology & Drug Design, vol. 78, no. 3, 2011, pp. 333-52.
Zeng H, Zhang H, Jang F, et al. Molecular modeling studies on benzimidazole carboxamide derivatives as PARP-1 inhibitors using 3D-QSAR and docking. Chem Biol Drug Des. 2011;78(3):333-52.
Zeng, H., Zhang, H., Jang, F., Zhao, L., & Zhang, J. (2011). Molecular modeling studies on benzimidazole carboxamide derivatives as PARP-1 inhibitors using 3D-QSAR and docking. Chemical Biology & Drug Design, 78(3), 333-52. https://doi.org/10.1111/j.1747-0285.2011.01139.x
Zeng H, et al. Molecular Modeling Studies On Benzimidazole Carboxamide Derivatives as PARP-1 Inhibitors Using 3D-QSAR and Docking. Chem Biol Drug Des. 2011;78(3):333-52. PubMed PMID: 21585709.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular modeling studies on benzimidazole carboxamide derivatives as PARP-1 inhibitors using 3D-QSAR and docking. AU - Zeng,Huahui, AU - Zhang,Huabei, AU - Jang,Fubin, AU - Zhao,Lingzhou, AU - Zhang,Jianyuan, Y1 - 2011/07/29/ PY - 2011/5/19/entrez PY - 2011/5/19/pubmed PY - 2011/12/13/medline SP - 333 EP - 52 JF - Chemical biology & drug design JO - Chem Biol Drug Des VL - 78 IS - 3 N2 - 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. SN - 1747-0285 UR - https://www.unboundmedicine.com/medline/citation/21585709/Molecular_modeling_studies_on_benzimidazole_carboxamide_derivatives_as_PARP_1_inhibitors_using_3D_QSAR_and_docking_ DB - PRIME DP - Unbound Medicine ER -