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Bioorg Med Chem Lett. 2011 Sep 15;21(18):5460-4. doi: 10.1016/j.bmcl.2011.06.123. Epub 2011 Jul 2.

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

Author information

1
Leiden/Amsterdam Center of Drug Research, Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.

Abstract

A fragment library was screened against the G protein-coupled histamine H(4) receptor (H(4)R) and the ligand-gated ion channel serotonin 5-HT(3A) (5-HT(3A)R). Interestingly, significant overlap was found between H(4)R and 5-HT(3A)R hit sets. The data indicates that dual active H(4)R and 5 HT(3A)R 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 H(4)R and 5-HT(3A)R and have important consequences for selectivity profiling in ongoing drug discovery efforts on H(4)R and 5-HT(3A)R. The affinity profiles of our fragment screening studies furthermore match the chemical properties of the H(4)R and 5-HT(3A)R binding sites and can be used to define molecular interaction fingerprints to guide the in silico prediction of protein-ligand interactions and structure.

PMID:
21782429
PMCID:
PMC3235552
DOI:
10.1016/j.bmcl.2011.06.123
[Indexed for MEDLINE]
Free PMC Article

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