5I4V

Discovery of novel, orally efficacious Liver X Receptor (LXR) beta agonists

5I4V の概要

• エントリーDOI: 10.2210/pdb5i4v/pdb
• 分子名称: Oxysterols receptor LXR-beta,Nuclear receptor coactivator 2, Retinoic acid receptor RXR-beta,Nuclear receptor coactivator 2, {2-[(2R)-4-[4-(hydroxymethyl)-3-(methylsulfonyl)phenyl]-2-(propan-2-yl)piperazin-1-yl]-4-(trifluoromethyl)pyrimidin-5-yl}methanol, ... (4 entities in total)
• 機能のキーワード: lxrbeta-lbd, rxrbeta-lbd, heterodimer, agonist, dna binding protein
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Nucleus: Q15596 Q15596
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 118341.54

構造登録者

Chen, G.,McKeever, B.M. (登録日: 2016-02-12, 公開日: 2016-06-29, 最終更新日: 2023-09-27)

主引用文献

Zheng, Y.,Zhuang, L.,Fan, K.Y.,Tice, C.M.,Zhao, W.,Dong, C.,Lotesta, S.D.,Leftheris, K.,Lindblom, P.R.,Liu, Z.,Shimada, J.,Noto, P.B.,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, B.M.,McGeehan, G.M.,Gregg, R.E.,Claremon, D.A.,Singh, S.B.
Discovery of a Novel, Orally Efficacious Liver X Receptor (LXR) beta Agonist.
J.Med.Chem., 59:3264-3271, 2016

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

PubMed: 26990539
DOI: 10.1021/acs.jmedchem.5b02029

実験手法

X-RAY DIFFRACTION (2.61 Å)