Pharmacophore Modeling and Virtual Screening Studies of Checkpoint Kinase 1 Inhibitors
In this study, chemical feature-based 3-dimensional (3D) pharmacophore models of Checkpoint kinase 1 (Chk1) inhibitors were developed based on the known inhibitors of Chkl. The best pharmacophore model Hypo1 was characterized by the best correlation coefficient (0.9577), and the lowest root mean square deviation (0.8871). Hypol consists of one hydrogenbond acceptor, one hydrogen-bond donor, and two bydrophobic features, as well as one excluded volume. This pharmacophore model was further validated by both test set and cross validation methods. A comparison analysis of Hypol with chemical features in the active site of Chkl indicates that the pharmacophore model Hypol can correctly reflect the interactions between Chkl and its ligands. Then Hypol was used to screen chemical databases, including Specs and Chinese Nature Product Database (CNPD) for potential lead compounds. The hit compounds were subsequently subjected to filtering by Lipinskis rule of five and docking study to refine the retrieved hits. Finally some of the most potent (estimated) compounds were selected from the final refined hits and suggested for further experimental investigation.
Jin-Juan Chen Ting-Lin Liu Li-Jun Yang Lin-Li Li Yu-Quan Wei Sheng-Yong Yang
State Key Laboratory of Biotherapy, West China Hospital, West China School of Pharmacy, Sichuan University, Sichuan 610041, China
国际会议
武汉
英文
59-64
2010-09-01（万方平台首次上网日期，不代表论文的发表时间）