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Discovery, optimization and biological evaluation for novel c-Met kinase inhibitors.

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.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Yuan H,Liu Q,Zhang L,Hu S,Chen T,Li H,Chen Y,Xu Y,Lu T

doi

10.1016/j.ejmech.2017.11.073

subject

Has Abstract

pub_date

2018-01-01 00:00:00

pages

491-502

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(17)30976-5

journal_volume

143

pub_type

杂志文章

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