Pharmacophore modeling and virtual screening studies to identify new c-Met inhibitors

Abstract

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.

In silico study of subtilisin-like protease 1 (SUB1) from different Plasmodium species in complex with peptidyl-difluorostatones and characterization of potent pan-SUB1 inhibitors

“…Next, we performed a preliminary in silico validation of our SUB1-PHA using a pharmacophore validation method based on the generation of decoys set, a procedure largely used to assess the ability of pharmacophore models to discriminate between active or inactive molecules [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] . Starting from compounds 1 and 2 (superposed to the SUB1-PHA in Fig.…”

Cheminfomatic-based Drug Discovery of Human Tyrosine Kinase Inhibitors

“…[79] and Tai et al . [80] have been reported. Albeit the fact that the algorithms/software used by both groups were different and their data sets were structurally diverse and independent of each other, the final conclusions of both appear to be similar.…”

Identification of Phytochemicals Targeting c-Met Kinase Domain using Consensus Docking and Molecular Dynamics Simulation Studies

“…Receptor tyrosine kinases (RTKs) are pharmaceutically attractive targets for this purpose because they play a critical role in tumor formation. They regulate a variety of signal-transduction pathways within a cell [2], of which c-Met and its ligand, hepatocyte growth factor (HGF), mediate epithelial tissue remodeling, migration, morphogenesis, cell growth, differentiation, and angiogenesis [2,3]. Deregulated activation of c-Met-signaling pathway through multiple mechanisms like activation, mutation, gene amplification, and heterodimerization has been reported to correlate with high tumor grade and lower rate of survival in most cancers [3,4].…”

“…Two distinct binding patterns have been proposed for these ATP-competitive inhibitors: type I compounds (e.g., PF-023410661) bind to activated DFG-in conformation and interact with Met 1160 in the hinge region and Tyr 1230 in the activation loop. Although they are specific, they display limited activity toward Tyr 1230 mutation, while type II compounds (e.g., BMS-777607) are less selective and bind in the inactive DFG-out conformation formed by conformational changes of the Asp1222 side chain [2,3,7].…”