Abstract

Structure Based Drug Design of Tryptophan Hydroxylase (TPH) Inhibitors Exploiting the Binding Pocket of the Co-Substrate Pterin

Edgar Specker, Head of Compound Management, Medicinal Chemistry Group, Leibniz Institute of Molecular Pharmacology

Within mammalian organisms, tryptophan hydroxylases (TPH) catalyze the rate-limiting step in the biosynthesis of the hormone and neurotransmitter serotonin. Elevated peripheral serotonin levels are linked to pulmonary hypertension, osteoporosis and gastrointestinal disorders like irritable bowel disease and colitis, calling for the development of TPH inhibitors. Here we present our joint collaborative research effort screening the FMP compound library in a high throughput campaign which led to the identification of initial hits. After hit validation a focused library was synthesized and the structurally related compounds were optimized by means of a structure guided drug design process. A novel binding mode of the synthesized compounds was observered and suitable subpockets were exploited to improve the affinity of the inhibitors. More than 10 inhibitor-enzyme-complexes were successfully determined for TPH1 and TPH2, respectively, at resolutions of up to 1.4 Å. Selected inhibitors were profiled for their in vitro ADME properties and will be further used in respective animal models to study their protective effect on the formation and progression of pulmonary hypertension. In summary, we successfully established a novel class of xanthine derivatives as TPH inhibitors that can potentially be used as pharmaceutical agents in the treatment of serotonin-related diseases.