Energetic factors determining the binding of type I inhibitors to c-Met kinase: experimental studies and quantum mechanical calculations.
OBJECTIVE
To decipher the molecular interactions between c-Met and its type I inhibitors and to facilitate the design of novel c-Met inhibitors.


METHODS
Based on the prototype model inhibitor 1, four ligands with subtle differences in the fused aromatic rings were synthesized. Quantum chemistry was employed to calculate the binding free energy for each ligand. Symmetry-adapted perturbation theory (SAPT) was used to decompose the binding energy into several fundamental forces to elucidate the determinant factors.


RESULTS
Binding free energies calculated from quantum chemistry were correlated well with experimental data. SAPT calculations showed that the predominant driving force for binding was derived from a sandwich π-π interaction with Tyr-1230. Arg-1208 was the differentiating factor, interacting with the 6-position of the fused aromatic ring system through the backbone carbonyl with a force pattern similar to hydrogen bonding. Therefore, a hydrogen atom must be attached at the 6-position, and changing the carbon atom to nitrogen caused unfavorable electrostatic interactions.


CONCLUSIONS
The theoretical studies have elucidated the determinant factors involved in the binding of type I inhibitors to c-Met.
1] State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [2] Shenyang Pharmaceutical University, School of Pharmaceutical Engineering, Shenyang 110016, China.
Zhe
Z
Yu
Yu-chi
YC
Ma
Jing
J
Ai
Dan-qi
DQ
Chen
Dong-mei
DM
Zhao
Xin
X
Wang
Yue-lei
YL
Chen
Mei-yu
MY
Geng
Bing
B
Xiong
Mao-sheng
MS
Cheng
Jing-Kang
JK
Shen
D015195:Drug Design; D006860:Hydrogen Bonding; D008024:Ligands; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011789:Quantum Theory; D055672:Static Electricity
D008024:Ligands; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met