5YA5

CRYSTAL STRUCTURE OF c-MET IN COMPLEX WITH NOVEL INHIBITOR

Summary for 5YA5

• Entry DOI: 10.2210/pdb5ya5/pdb
• Descriptor: Hepatocyte growth factor receptor, 2-[3-(4-methoxybenzyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl]-1H-indole (3 entities in total)
• Functional Keywords: c-met inhibitor, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 36395.01

Authors

Liu, Q.,Xu, Y. (deposition date: 2017-08-30, release date: 2018-07-04, Last modification date: 2023-11-22)

Primary citation

Yuan, H.,Liu, Q.,Zhang, L.,Hu, S.,Chen, T.,Li, H.,Chen, Y.,Xu, Y.,Lu, T.
Discovery, optimization and biological evaluation for novel c-Met kinase inhibitors
Eur J Med Chem, 143:491-502, 2018

PubMed Abstract: The c-Met kinase has emerged as an attractive target for developing antitumor agents because of its close relationship with the development of many human cancers, poor clinical outcomes and even drug resistance. A series of novel c-Met kinase inhibitors have been identified with multiple workflow in this work, including virtual screening, X-ray crystallography, biological evaluation and structural optimization. The experimentally determined crystal structure of the best hit compound HL-11 in c-Met kinase domain was highly consistent with the computational prediction. Comparison of the hit compounds with different c-Met kinase inhibitory activity by molecular dynamics simulations suggested the key protein-ligand interactions for structural optimization. Based on these, structural optimization produced compound 11e with better c-Met kinase inhibitory activity and improved anti-proliferative activity. These experimental findings proved the reliability and efficiency of our in silico methods. This strategy will facilitate further lead discovery and optimization for novel c-Met kinase inhibitors.

PubMed: 29202410
DOI: 10.1016/j.ejmech.2017.11.073

Experimental method

X-RAY DIFFRACTION (1.89 Å)