6R8O

Human Cyclophilin D in complex with 1-(((2R,3S,6R)-3-hydroxy-2,3,4,6-tetrahydro-1H-2,6-methanobenzo[c][1,5]oxazocin-8-yl)methyl)-3-(2-((R)-2-(2-(methylthio)phenyl)pyrrolidin-1-yl)-2-oxoethyl)urea

6R8O の概要

• エントリーDOI: 10.2210/pdb6r8o/pdb
• 分子名称: Peptidyl-prolyl cis-trans isomerase F, mitochondrial, TETRAETHYLENE GLYCOL, SULFATE ION, ... (6 entities in total)
• 機能のキーワード: cyclophilin, beta barrel, prolyl cis/trans isomerase, mitoc, isomerase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18534.01

構造登録者

Graedler, U. (登録日: 2019-04-02, 公開日: 2019-11-27, 最終更新日: 2024-01-24)

主引用文献

Gradler, U.,Schwarz, D.,Blaesse, M.,Leuthner, B.,Johnson, T.L.,Bernard, F.,Jiang, X.,Marx, A.,Gilardone, M.,Lemoine, H.,Roche, D.,Jorand-Lebrun, C.
Discovery of novel Cyclophilin D inhibitors starting from three dimensional fragments with millimolar potencies.
Bioorg.Med.Chem.Lett., 29:126717-126717, 2019

PubMed Abstract: Fragment-based screening by SPR enabled the discovery of chemical diverse fragment hits with millimolar binding affinities to the peptidyl-prolyl isomerase Cyclophilin D (CypD). The CypD protein crystal structures of 6 fragment hits provided the basis for subsequent medicinal chemistry optimization by fragment merging and linking yielding three different chemical series with either urea, oxalyl or amide linkers connecting millimolar fragments in the S1' and S2 pockets. We successfully improved the in vitro CypD potencies in the biochemical FP and PPIase assays and in the biophysical SPR binding assay from millimolar towards the low micromolar and submicromolar range by >1000-fold for some fragment derivatives. The initial SAR together with the protein crystal structures of our novel CypD inhibitors provide a suitable basis for further hit-to-lead optimization.

PubMed: 31635932
DOI: 10.1016/j.bmcl.2019.126717

実験手法

X-RAY DIFFRACTION (1.36 Å)