期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 59, 期 7, 页码 3264-3271出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b02029
关键词
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资金
- NIGMS NIH HHS [P41 GM111244] Funding Source: Medline
This article describes the application of Contour to the design and discovery of a novel, potent, orally efficacious liver X receptor beta (LXR beta) agonist (17). Contour technology is a structure-based drug design platform that generates molecules using a context perceptive growth algorithm guided by a contact sensitive scoring function. The growth engine uses binding site perception and programmable growth capability to create drug-like molecules by assembling fragments that naturally complement hydrophilic and hydrophobic features of the protein binding site. Starting with a crystal structure of LXR beta and a docked 2-(methylsulfonyl)benzyl alcohol fragment (6), Contour was used to design agonists containing a piperazine core. Compound 17 binds to LXR beta with high affinity and to LXR alpha to a lesser extent, and induces the expression of LXR target genes in vitro and in vivo. This molecule served as a starting point for further optimization and generation of a candidate which is currently in human clinical trials for treating atopic dermatitis.
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