Lu Shuai, Liu Hai-Chun, Chen Ya-Dong, Yuan Hao-Liang, Sun Shan-Liang, Gao Yi-Ping, Yang Pei, Zhang Liang, Lu Tao
Laboratory of Molecular Design and Drug Discovery, China Pharmaceutical University, Nanjing 211169, China.
Int J Mol Sci. 2011;12(12):8713-39. doi: 10.3390/ijms12128713. Epub 2011 Dec 1.
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 q(2) and r(2) (pred) 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.
Polo样激酶1是一种在细胞有丝分裂中具有多种生物学作用的重要酶,是开发新型抗癌药物的一个有前景的靶点。对一组作为PLK1抑制剂的4,5-二氢-1H-吡唑并[4,3-h]喹唑啉衍生物进行了分子对接、基于结构的药效团建模和三维定量构效关系(3D-QSAR)的联合研究。利用共同子结构、分子对接和基于药效团的比对来开发不同的3D-QSAR模型。比较分子场分析(CoMFA)和比较分子相似性指数分析(CoMSIA)模型给出了具有统计学意义的结果。这些模型显示出良好的q(2)和r(2)(预测)值,并对测试集验证表现出良好的响应。从3D-QSAR等高线图获得的所有结构见解都与PLK1的现有晶体结构一致。从3D-QSAR模型获得的等高线图与基于结构的药效团模型相结合,有助于更好地解释构效关系。这些令人满意的结果可能有助于新型PLK1抑制剂的设计。这是关于PLK1抑制剂3D-QSAR研究的首次报道。