This study utilizes the comprehensive traditional Chinese medicine database TCM Database@Taiwan ( http://tcm.cmu.edu.tw/ ) in conjunction with structure-based and ligand-based drug design to identify multi-function Src inhibitors. The three potential TCM candidates identified as having suitable docking conformations and bioactivity profiles were Angeliferulate, (3R)-2'-hydroxy-3',4'-dimethoxyisoflavan-7-O-beta-D-glucoside (HMID), and 3-[2',6-dihydroxy-5'-(2-propenyl)[1,1'-biphenyl]3-yl]-(E)-2-propenoic acid (3PA). Molecular dynamics simulation demonstrated that the TCM candidates have more stable interactions with the cleft and in complex with Src kinase compared to Saracatinib. Angeliferulate and HMID, both originated from Angelica sinensis, not only interact with Lys298 and amino acids from different loops in the cleft, but also with Asp407 located on the activation loop. These interactions are important to reduce the opening of the activation loop due to phosphorylation, hence stabilize the Src kinase cleft structure and inhibit activation. The TCM candidates also exhibited high affinity to other cancer-related target proteins (EGFR, HER2, and HSP90). Our observations suggest that the TCM candidates might have multi-targeting effects in hypertension and cancer.
