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Fragment library screening reveals remarkable similarities between the G protein-coupled receptor histamine H4 and the ion channel serotonin 5-HT3A

By Mark H.P. Verheij, Chris de Graaf, Gerdien E. de Kloe, Saskia Nijmeijer, Henry F. Vischer, Rogier A. Smits, Obbe P. Zuiderveld, Saskia Hulscher, Linda Silvestri, Andrew J. Thompson, Jacqueline E. van Muijlwijk-Koezen, Sarah C.R. Lummis, Rob Leurs and Iwan J.P. de Esch

Abstract

A fragment library was screened against the G protein-coupled histamine H4 receptor (H4R) and the ligand-gated ion channel serotonin 5-HT3A (5-HT3AR). Interestingly, significant overlap was found between H4R and 5-HT3AR hit sets. The data indicates that dual active H4R and 5 HT3AR fragments have a higher complexity than the selective compounds which has important implications for chemical genomics approaches. The results of our fragment-based library screening study illustrate similarities in ligand recognition between H4R and 5-HT3AR and have important consequences for selectivity profiling in ongoing drug discovery efforts on H4R and 5-HT3AR. The affinity profiles of our fragment screening studies furthermore match the chemical properties of the H4R and 5-HT3AR binding sites and can be used to define molecular interaction fingerprints to guide the in silico prediction of protein-ligand interactions and structure

Topics: Article
Publisher: Elsevier Science Ltd
OAI identifier: oai:pubmedcentral.nih.gov:3235552
Provided by: PubMed Central
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