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Structure-based de novo design and identification of D816V mutant-selective c-KIT inhibitors

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Title
Structure-based de novo design and identification of D816V mutant-selective c-KIT inhibitors
Author(s)
Hwangseo Park; Soyoung Lee; Suhyun Lee; Sung Woo Hong
Publication Date
2014-07
Journal
ORGANIC & BIOMOLECULAR CHEMISTRY, v.12, no.26, pp.4644 - 4655
Publisher
ROYAL SOC CHEMISTRY
Abstract
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.
URI
https://pr.ibs.re.kr/handle/8788114/989
ISSN
1477-0520
Appears in Collections:
Center for Catalytic Hydrocarbon Functionalizations(분자활성 촉매반응 연구단) > Journal Papers (저널논문)
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