Combined Structure-Based Pharmacophore and 3D-QSAR Studies on Phenylalanine Series Compounds as TPH1 Inhibitors

Liang Ouyang,Wei Huang,Gu He,Xiangrong Song,Mingli Xiang,Fengbo Wu

doi:10.3390/ijms13055348

Abstract

Tryptophan hydroxylase-1 (TPH1) is a key enzyme in the synthesis of serotonin. As a neurotransmitter, serotonin plays important physiological roles both peripherally and centrally. In this study, a combination of ligand-based and structure-based methods is used to clarify the essential quantitative structure-activity relationship (QSAR) of known TPH1 inhibitors. A multicomplex-based pharmacophore (MCBP) guided method has been suggested to generate a comprehensive pharmacophore of TPH1 kinase based on three crystal structures of TPH1-inhibitor complex. This model has been successfully used to identify the bioactive conformation and align 32 structurally diverse substituted phenylalanine derivatives. The QSAR analyses have been performed on these TPH1 inhibitors based on the MCBP guided alignment. These results may provide important information for further design and virtual screening of novel TPH1 inhibitors.

Highlights

Serotonin (5-hydroxytryptamine, 5-HT) is a monoamine neurotransmitter that modulates central and peripheral functions through action on platelets, smooth muscles, neurons, and other cellInt
It is believed that the pharmacophore features, which present in the complexes with a high probability, were likely to be more important than features that exhibit a low probability
We utilized 3 crystal structures of human Tryptophan hydroxylase-1 (TPH1) bound to small molecular inhibitors to generate a multicomplex-based pharmacophore

Summary

Introduction

Serotonin (5-hydroxytryptamine, 5-HT) is a monoamine neurotransmitter that modulates central and peripheral functions through action on platelets, smooth muscles, neurons, and other cellInt. Serotonin (5-hydroxytryptamine, 5-HT) is a monoamine neurotransmitter that modulates central and peripheral functions through action on platelets, smooth muscles, neurons, and other cell. The biosynthesis of Serotonin is limited by the hydroxylation of tryptophan which is catalyzed by tryptophan hydroxylase (TPH). In the GI system, TPH1 is primarily expressed and dysregulation of the peripheral 5-HT signaling system is involved in the etiology of several conditions such as functional GI disorders, chemotherapy-induced emesis, and heart valve damage [4,5]. Inhibitors of TPH1 have proven effective in treating chemotherapy-induced emesis, as well as diarrhea, in carcinoid tumor patients. Some pharmaceutical companies are developing candidate drug molecules based on this target for treating dysregulation of the serotonergic system, such as irritable bowel syndrome [6]

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