Engineering a region of bulk tolerance in the 5-HT2A receptor

Autor:	Naseem Khan, Mohammad S Choudhary, Edward G. Hyde, Richard B. Westkaemper, Edward I Gelbar, Bryan L. Roth, Richard A. Glennon
Rok vydání:	1999
Předmět:	Pharmacology Ketanserin Chemistry Stereochemistry Organic Chemistry Mutagenesis Mutant Antagonist Phenylalanine General Medicine Biochemistry Drug Discovery medicine Leucine Receptor Binding affinities medicine.drug
Zdroj:	European Journal of Medicinal Chemistry. 34:441-447
ISSN:	0223-5234
DOI:	10.1016/s0223-5234(99)80094-4
Popis:	Anew binding model for ketanserin was constructed; this model and preliminary mutagenesis data suggested that a highly conserved phenylalanine (F340) introduces a potential region of bulk-intolerance into the binding pocket. We tested this hypothesis by evaluating the binding affinities of several novel analogues of the 5-HT2A antagonist ketanserin at both native and mutant receptors. We found that replacing the bulky F340 with a less bulky leucine (F340L) dramatically enhances (37 ± 16-fold; P 0.05 vs. native receptor). This structural modification of the receptor allowed for the increased affinity of low-affinity, bulky ketanserin analogues.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::1f4d3c972daadbe55c379425482b4fc5 https://doi.org/10.1016/s0223-5234(99)80094-4 Zobrazit plný text záznamu Full Text from ScienceDirect