6GWE

Crystal structure of Thrombin bound to P2 macrocycle

6GWE の概要

• エントリーDOI: 10.2210/pdb6gwe/pdb
• 分子名称: Thrombin heavy chain, Thrombin light chain, (10S,14S,17R)-14-(3-carbamimidamidopropyl)-3-[[2-(hydroxymethyl)phenyl]methyl]-5,12,15-tris(oxidanylidene)-19-thia-3,6,13,16-tetrazatricyclo[19.4.0.0^{6,10}]pentacosa-1(21),22,24-triene-17-carboxamide, ... (7 entities in total)
• 機能のキーワード: serine portease, blood coagulation, hydrolase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 69823.84

構造登録者

Cendron, L.,Angelini, A.,Kale, S.S.,Bergeron-Brlek, M.,Wu, Y.,Heinis, C. (登録日: 2018-06-23, 公開日: 2019-09-25, 最終更新日: 2024-11-13)

主引用文献

Kale, S.S.,Bergeron-Brlek, M.,Wu, Y.,Kumar, M.G.,Pham, M.V.,Bortoli, J.,Vesin, J.,Kong, X.D.,Machado, J.F.,Deyle, K.,Gonschorek, P.,Turcatti, G.,Cendron, L.,Angelini, A.,Heinis, C.
Thiol-to-amine cyclization reaction enables screening of large libraries of macrocyclic compounds and the generation of sub-kilodalton ligands.
Sci Adv, 5:eaaw2851-eaaw2851, 2019

PubMed Abstract: Macrocyclic compounds are an attractive modality for drug development, but the limited availability of large, structurally diverse macrocyclic libraries hampers the discovery of leads. Here, we describe the discovery of efficient macrocyclization reactions based on thiol-to-amine ligations using bis-electrophiles, their application to synthesize and screen large libraries of macrocyclic compounds, and the identification of potent small macrocyclic ligands. The thiol-to-amine cyclization reactions showed unexpectedly high yields for a wide substrate range, which obviated product purification and enabled the generation and screening of an 8988 macrocycle library with a comparatively small effort. X-ray structure analysis of an identified thrombin inhibitor ( = 42 ± 5 nM) revealed a snug fit with the target, validating the strategy of screening large libraries with a high skeletal diversity. The approach provides a route for screening large sub-kilodalton macrocyclic libraries and may be applied to many challenging drug targets.

PubMed: 31457083
DOI: 10.1126/sciadv.aaw2851

実験手法

X-RAY DIFFRACTION (2.3 Å)