8cjl

Crystal structure of human tryptophan hydroxylase 1 in complex with inhibitor TPT-004

spinqualitylabelsall models 8cjl, resolution 1.83Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8cjl is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.83Å Ligands: FE, UXC Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function TPH1_HUMAN Publication Abstract from PubMed 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 32 (TPT-004) shows superior pharmacokinetic and pharmacodynamic properties as well as efficacy in preclinical models of peripheral serotonin attenuation and colorectal tumor growth. Structure-Based Design of Xanthine-Imidazopyridines and -Imidazothiazoles as Highly Potent and In Vivo Efficacious Tryptophan Hydroxylase Inhibitors.,Specker E, Wesolowski R, Schutz A, Matthes S, Mallow K, Wasinska-Kalwa M, Winkler L, Oder A, Alenina N, Pleimes D, von Kries JP, Heinemann U, Bader M, Nazare M J Med Chem. 2023 Nov 9;66(21):14866-14896. doi: 10.1021/acs.jmedchem.3c01454. , Epub 2023 Oct 31. PMID:37905925 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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