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Combined Pharmacophore Modeling, Docking, and 3D-QSAR Studies of PLK1 Inhibitors
Laboratory of Molecular Design and Drug Discovery, China Pharmaceutical University, Nanjing 211169, China
Department of Organic Chemistry, China Pharmaceutical University, Nanjing 211169, China
School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211169, China
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211169, China
* Authors to whom correspondence should be addressed.
Received: 4 September 2011; in revised form: 1 November 2011 / Accepted: 21 November 2011 / Published: 1 December 2011
Abstract: Polo-like kinase 1, an important enzyme with diverse biological actions in cell mitosis, is a promising target for developing novel anticancer drugs. A combined molecular docking, structure-based pharmacophore modeling and three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on a set of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as PLK1 inhibitors. The common substructure, molecular docking and pharmacophore-based alignment were used to develop different 3D-QSAR models. The comparative molecular field analysis (CoMFA) and comparative molecule similarity indices analysis (CoMSIA) models gave statistically significant results. These models showed good q2 and r2pred values and revealed a good response to test set validation. All of the structural insights obtained from the 3D-QSAR contour maps are consistent with the available crystal structure of PLK1. The contour maps obtained from the 3D-QSAR models in combination with the structure based pharmacophore model help to better interpret the structure-activity relationship. These satisfactory results may aid the design of novel PLK1 inhibitors. This is the first report on 3D-QSAR study of PLK1 inhibitors.
Keywords: PLK1; 3D-QSAR; pharmacophore; molecular docking
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MDPI and ACS Style
Lu, S.; Liu, H.-C.; Chen, Y.-D.; Yuan, H.-L.; Sun, S.-L.; Gao, Y.-P.; Yang, P.; Zhang, L.; Lu, T. Combined Pharmacophore Modeling, Docking, and 3D-QSAR Studies of PLK1 Inhibitors. Int. J. Mol. Sci. 2011, 12, 8713-8739.
Lu S, Liu H-C, Chen Y-D, Yuan H-L, Sun S-L, Gao Y-P, Yang P, Zhang L, Lu T. Combined Pharmacophore Modeling, Docking, and 3D-QSAR Studies of PLK1 Inhibitors. International Journal of Molecular Sciences. 2011; 12(12):8713-8739.
Lu, Shuai; Liu, Hai-Chun; Chen, Ya-Dong; Yuan, Hao-Liang; Sun, Shan-Liang; Gao, Yi-Ping; Yang, Pei; Zhang, Liang; Lu, Tao. 2011. "Combined Pharmacophore Modeling, Docking, and 3D-QSAR Studies of PLK1 Inhibitors." Int. J. Mol. Sci. 12, no. 12: 8713-8739.