Novel inhibitors induce large conformational changes of GAB1 pleckstrin homology domain and kill breast cancer cells.

ABSTRACT: The Grb2-associated binding protein 1 (GAB1) integrates signals from different signaling pathways and is over-expressed in many cancers, therefore representing a new therapeutic target. In the present study, we aim to target the pleckstrin homology (PH) domain of GAB1 for cancer treatment. Using homology models we derived, high-throughput virtual screening of five million compounds resulted in five hits which exhibited strong binding affinities to GAB1 PH domain. Our prediction of ligand binding affinities is also in agreement with the experimental KD values. Furthermore, molecular dynamics studies showed that GAB1 PH domain underwent large conformational changes upon ligand binding. Moreover, these hits inhibited the phosphorylation of GAB1 and demonstrated potent, tumor-specific cytotoxi

SUBMITTER: Chen L 

PROVIDER: S-EPMC4287437 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature