6ESN

Ligand complex of RORg LBD

6ESN の概要

• エントリーDOI: 10.2210/pdb6esn/pdb
• 分子名称: Nuclear receptor ROR-gamma, LYS-HIS-LYS-ILE-LEU-HIS-ARG-LEU-LEU-GLN-ASP-SER, (2~{R})-2-acetamido-~{N}-[4-(5-cyano-3-fluoranyl-2-methoxy-phenyl)thiophen-2-yl]-2-(4-ethylsulfonylphenyl)ethanamide, ... (5 entities in total)
• 機能のキーワード: rar-related orphan receptor-g (rorg), transcription, rorg ligand, structure-based design
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 33063.95

構造登録者

Xue, Y.,Aagaard, A.,Narjes, F. (登録日: 2017-10-23, 公開日: 2018-08-22, 最終更新日: 2024-05-08)

主引用文献

Narjes, F.,Xue, Y.,von Berg, S.,Malmberg, J.,Llinas, A.,Olsson, R.I.,Jirholt, J.,Grindebacke, H.,Leffler, A.,Hossain, N.,Lepisto, M.,Thunberg, L.,Leek, H.,Aagaard, A.,McPheat, J.,Hansson, E.L.,Back, E.,Tangefjord, S.,Chen, R.,Xiong, Y.,Hongbin, G.,Hansson, T.G.
Potent and Orally Bioavailable Inverse Agonists of ROR gamma t Resulting from Structure-Based Design.
J. Med. Chem., 61:7796-7813, 2018

PubMed Abstract: Retinoic acid receptor related orphan receptor γt (RORγt), has been identified as the master regulator of T17-cell function and development, making it an attractive target for the treatment of autoimmune diseases by a small-molecule approach. Herein, we describe our investigations on a series of 4-aryl-thienyl acetamides, which were guided by insights from X-ray cocrystal structures. Efforts in targeting the cofactor-recruitment site from the 4-aryl group on the thiophene led to a series of potent binders with nanomolar activity in a primary human-T17-cell assay. The observation of a DMSO molecule binding in a subpocket outside the LBD inspired the introduction of an acetamide into the benzylic position of these compounds. Hereby, a hydrogen-bond interaction of the introduced acetamide oxygen with the backbone amide of Glu379 was established. This greatly enhanced the cellular activity of previously weakly cell-active compounds. The best compounds combined potent inhibition of IL-17 release with favorable PK in rodents, with compound 32 representing a promising starting point for future investigations.

PubMed: 30095900
DOI: 10.1021/acs.jmedchem.8b00783

実験手法

X-RAY DIFFRACTION (1.84 Å)