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Publication Abstract from PubMed

This article describes the application of Contour to the design and discovery of a novel, potent, orally efficacious liver X receptor beta (LXRbeta) 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 LXRbeta and a docked 2-(methylsulfonyl)benzyl alcohol fragment (6), Contour was used to design agonists containing a piperazine core. Compound 17 binds to LXRbeta with high affinity and to LXRalpha 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.

Discovery of a Novel, Orally Efficacious Liver X Receptor (LXR) beta Agonist.,Zheng Y, Zhuang L, Fan KY, Tice CM, Zhao W, Dong C, Lotesta SD, Leftheris K, Lindblom PR, Liu Z, Shimada J, Noto PB, Meng S, Hardy A, Howard L, Krosky P, Guo J, Lipinski K, Kandpal G, Bukhtiyarov Y, Zhao Y, Lala D, Van Orden R, Zhou J, Chen G, Wu Z, McKeever BM, McGeehan GM, Gregg RE, Claremon DA, Singh SB J Med Chem. 2016 Apr 14;59(7):3264-71. doi: 10.1021/acs.jmedchem.5b02029. Epub, 2016 Mar 29. PMID:26990539^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.