Structure-based de novo design and identification of D816V mutant-selective c-KIT inhibitors.
To identify potent and selective inhibitors of D816V, the most common gain-of-function c-KIT mutant, we carried out structure-based de novo design using 7-azaindole as the core and the scoring function improved by implementing an accurate solvation free energy term. This approach led to the identification of new c-KIT inhibitors specific for the D816V mutant. The 3-(3,4-dimethoxyphenyl)-7-azaindole scaffold was optimized and represents a lead structure for the design of the potent and specific inhibitors of the D816V mutant. The results of molecular dynamics simulations indicate that hydrogen bonding interactions between the 7-azadindole moiety and the backbone groups of Cys673 are the most significant determinant for the potency and selectivity of c-KIT inhibitors.
Department of Bioscience and Biotechnology, Sejong University, Seoul, 143-747, Korea. hspark@sejong.ac.kr.
Hwangseo
H
Park
Soyoung
S
Lee
Suhyun
S
Lee
Sungwoo
S
Hong
D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D015195:Drug Design; D006860:Hydrogen Bonding; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D050505:Mutant Proteins / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013997:Time Factors
D007211:Indoles; D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D019009:Proto-Oncogene Proteins c-kit