Combined Pharmacophore Modeling, Docking, and 3D-QSAR Studies of PLK1 Inhibitors

• Main Authors: Tao Lu, Liang Zhang, Yi-Ping Gao, Pei Yang, Hao-Liang Yuan, Shan-Liang Sun, Shuai Lu, Ya-Dong Chen, Hai-Chun Liu
• Format: Article
• Language: English
• Published: MDPI AG 2011-12-01
• Series: International Journal of Molecular Sciences
• Subjects: PLK1; 3D-QSAR; pharmacophore; molecular docking
• Online Access: http://www.mdpi.com/1422-0067/12/12/8713/

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.