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 Chk1. The best pharmacophore model Hypo1 was characterized by the best correlation coefficient (0.9577), and the lowest root mean square deviation (0.8871). Hypo1 consists of one hydrogen-bond acceptor, one hydrogen-bond donor, and two hydrophobic 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 Hypo1 with chemical features in the active site of Chk1 indicates that the pharmacophore model Hypo1 can correctly reflect the interactions between Chk1 and its ligands. Then Hypo1 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 Lipinski's 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.
Chen
Jin-Juan
JJ
State Key Laboratory of Biotherapy, West China Hospital, West China School of Pharmacy, Sichuan University.
Liu
Ting-Lin
TL
Yang
Li-Jun
LJ
Li
Lin-Li
LL
Wei
Yu-Quan
YQ
Yang
Sheng-Yong
SY
D020134:Catalytic Domain; D000071877:Checkpoint Kinase 1; D020650:Combinatorial Chemistry Techniques; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008956:Models, Chemical; D008958:Models, Molecular; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1