Discovery of noveI EphB4 inhibitors based on pharmacophore modeIing and virtuaI screening techniques / 中国药科大学学报

ABSTRACT

The objective of this paper is to discover new potent inhibitors against EphB4 for cancer therapy via computer-aided drug design strategies including building 3D-QSAR models,virtual screening and molecular doc-king means.The first step is to generate pharmacophore models based on Catalyst/HypoGen algorithm.The best model,Hypo1,has the highest Correl value (0.96),the lowest RMS value (0.89),the closest total cost (101.26) to fixed cost (89.20),and the best Δcost (89.14).Subsequently,Hypo1 was subjected to test set validation and Fischer′s randomization verification and then was used as a 3D query to screen database.In order to further nar-row the number of hits,drug-likeness screening and molecular docking techniques were applied.Finally,23 novel molecules with diverse scaffolds were selected as possible candidates against EphB4 for further studies based on predicted activity analysis,docking scores,and binding modes analysis methods.