Pharmacophore modeling and virtual screening studies to identify new c-Met inhibitors.
Mesenchymal epithelial transition factor (c-Met) is an attractive target for cancer therapy. Three-dimensional pharmacophore hypotheses were built based on a set of known structurally diverse c-Met inhibitors. The best pharmacophore model, which identified inhibitors with an associated correlation coefficient of 0.983 between their experimental and estimated IC(50) values, consisted of two hydrogen-bond acceptors, one hydrophobic, and one ring aromatic feature. The highly predictive power of the model was rigorously validated by test set prediction and Fischer's randomization method. The high values of enrichment factor and receiver operating characteristic (ROC) score indicated the model performed fairly well at distinguishing active from inactive compounds. The model was then applied to screen compound database for potential c-Met inhibitors. A filtering protocol, including druggability and molecular docking, were also applied in hits selection. The final 38 molecules, which exhibited good estimated activities, desired binding mode and favorable drug likeness were identified as potential c-Met inhibitors. Their novel backbone structures could be served as scaffolds for further study, which may facilitate the discovery and rational design of potent c-Met kinase inhibitors.
Laboratory of Molecular Design and Drug Discovery, School of Basic Science, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
Wenting
W
Tai
Tao
T
Lu
Haoliang
H
Yuan
Fengxiao
F
Wang
Haichun
H
Liu
Shuai
S
Lu
Ying
Y
Leng
Weiwei
W
Zhang
Yulei
Y
Jiang
Yadong
Y
Chen
D003198:Computer Simulation; D016208:Databases, Factual; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D012372:ROC Curve; D015203:Reproducibility of Results
D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met