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Issue 26, 2014
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Structure-based de novo design and identification of D816V mutant-selective c-KIT inhibitors

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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.

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

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Publication details

The article was received on 08 Jan 2014, accepted on 30 Jan 2014 and first published on 22 May 2014


Article type: Paper
DOI: 10.1039/C4OB00053F
Author version available: Download Author version (PDF)
Citation: Org. Biomol. Chem., 2014,12, 4644-4655
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    Structure-based de novo design and identification of D816V mutant-selective c-KIT inhibitors

    H. Park, S. Lee, S. Lee and S. Hong, Org. Biomol. Chem., 2014, 12, 4644
    DOI: 10.1039/C4OB00053F

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