8CJK

Crystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-06-098

8CJK の概要

• エントリーDOI: 10.2210/pdb8cjk/pdb
• 分子名称: Tryptophan 5-hydroxylase 1, FE (III) ION, 3-ethyl-8-[(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)methyl]-7-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]purine-2,6-dione, ... (4 entities in total)
• 機能のキーワード: catalytic domain, tph1, inhibitor, metal binding protein
• 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: 37981.02

構造登録者

Schuetz, A.,Mallow, K.,Nazare, M.,Specker, E.,Heinemann, U. (登録日: 2023-02-13, 公開日: 2024-01-10)

主引用文献

Specker, E.,Wesolowski, R.,Schutz, A.,Matthes, S.,Mallow, K.,Wasinska-Kalwa, M.,Winkler, L.,Oder, A.,Alenina, N.,Pleimes, D.,von Kries, J.P.,Heinemann, U.,Bader, M.,Nazare, M.
Structure-Based Design of Xanthine-Imidazopyridines and -Imidazothiazoles as Highly Potent and In Vivo Efficacious Tryptophan Hydroxylase Inhibitors.
J.Med.Chem., 66:14866-14896, 2023

PubMed Abstract: Tryptophan hydroxylases catalyze the first and rate-limiting step in the biosynthesis of serotonin, a well-known neurotransmitter that plays an important role in multiple physiological functions. A reduction of serotonin levels, especially in the brain, can cause dysregulation leading to depression or insomnia. In contrast, overproduction of peripheral serotonin is associated with symptoms like carcinoid syndrome and pulmonary arterial hypertension. Recently, we developed a class of TPH inhibitors based on xanthine-benzimidazoles, characterized by a tripartite-binding mode spanning the binding sites of the cosubstrate pterin and the substrate tryptophan and by chelation of the catalytic iron ion. Herein, we describe the structure-based development of a second generation of xanthine-imidiazopyridines and -imidazothiazoles designed to inhibit TPH1 in the periphery while preventing the interaction with TPH2 in the brain. Lead compound (TPT-004) shows superior pharmacokinetic and pharmacodynamic properties as well as efficacy in preclinical models of peripheral serotonin attenuation and colorectal tumor growth.

PubMed: 37905925
DOI: 10.1021/acs.jmedchem.3c01454

実験手法

X-RAY DIFFRACTION (1.45914977372 Å)