Structure-based and ligand-based drug design for HER 2 receptor.
Human epidermal growth factor receptor 2, HER2, is a commonly over-expressed tyrosine kinase receptor found in many types of carcinoma. Despite that there are several HER2 inhibitors, namely Iressa, Tarceva and Tykerb, currently in clinical trials, all can cause several side effects. In this study, both structure-based and ligand-based drug design were employed to design novel HER2 inhibitors from traditional Chinese medicine (TCM). The HER2 structure model was built in homology modeling based on known receptors of the same family. Docking and de novo evolution experiments were performed to identify candidates and to build derivatives. A training set of 32 compounds with inhibitory activities to HER2 was used to formulate the pharmacophore hypotheses that were subsequently used to examine candidates obtained from the docking study. Hydrogen bond interactions, salt-bridge formations and pi-stacking were observed between the ligands and Phe731, Lys753, Asp863 and Asp808 of HER2 protein. Combining results from both docking and pharmacophore mapping analysis, CLC015-5, CLC604-11 and CLC604-18 were well accepted and consistent in both approaches and were considered as the most potential HER2 inhibitors.
Huang
Hung-Jin
HJ
Laboratory of Computational and Systems Biology, School of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan, ROC.
Lee
Kuei-Jen
KJ
Yu
Hsin W
HW
Chen
Chien-Yu
CY
Hsu
Chih-Ho
CH
Chen
Hsin-Yi
HY
Tsai
Fuu-Jen
FJ
Chen
Calvin Yu-Chian
CY
D000595:Amino Acid Sequence; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment
D008024:Ligands; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human