Cargando…
Functional group interactions of a 5-HT(3)R antagonist
BACKGROUND: Lerisetron, a competitive serotonin type 3 receptor (5-HT(3)R) antagonist, contains five functional groups capable of interacting with amino acids in the 5-HT(3)R binding site. Site directed mutagenesis studies of the 5-HT(3A)R have revealed several amino acids that are thought to form p...
Autores principales: | , , , , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2002
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC116678/ https://www.ncbi.nlm.nih.gov/pubmed/12079499 http://dx.doi.org/10.1186/1471-2091-3-16 |
_version_ | 1782120269063651328 |
---|---|
author | Venkataraman, Padmavati Joshi, Prasad Venkatachalan, Srinivasan P Muthalagi, Mani Parihar, Harish S Kirschbaum, Karen S Schulte, Marvin K |
author_facet | Venkataraman, Padmavati Joshi, Prasad Venkatachalan, Srinivasan P Muthalagi, Mani Parihar, Harish S Kirschbaum, Karen S Schulte, Marvin K |
author_sort | Venkataraman, Padmavati |
collection | PubMed |
description | BACKGROUND: Lerisetron, a competitive serotonin type 3 receptor (5-HT(3)R) antagonist, contains five functional groups capable of interacting with amino acids in the 5-HT(3)R binding site. Site directed mutagenesis studies of the 5-HT(3A)R have revealed several amino acids that are thought to form part of the binding domain of this receptor. The specific functional groups on the ligand that interact with these amino acids are, however, unknown. Using synthetic analogs of lerisetron as molecular probes in combination with site directed mutagenesis, we have identified some of these interactions and have proposed a model of the lerisetron binding site. RESULTS: Two analogs of lerisetron were synthesized to probe 5-HT(3)R functional group interactions with this compound. Analog 1 lacks the N1 benzyl group of lerisetron and analog 2 contains oxygen in place of the distal piperazine nitrogen. Both analogs show significantly decreased binding affinity to wildtype 5-HT(3AS)Rs. Mutations at W89, R91, Y142 and Y152 produced significant decreases in binding compared to wildtype receptors. Binding affinities of analogs 1 and 2 were altered only by mutations at W89, and Y152. CONCLUSIONS: Based on the data obtained for lerisetron and analogs 1 and 2, we have proposed a tentative model of the lerisetron binding pocket of the 5-HT(3AS)R. According to this model, The N-benzyl group interacts in a weak interaction with R91 while the benzimidazole group interacts with W89. Our data support an interaction of the distal amino nitrogen with Y142 and Y152. |
format | Text |
id | pubmed-116678 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2002 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-1166782002-07-05 Functional group interactions of a 5-HT(3)R antagonist Venkataraman, Padmavati Joshi, Prasad Venkatachalan, Srinivasan P Muthalagi, Mani Parihar, Harish S Kirschbaum, Karen S Schulte, Marvin K BMC Biochem Research Article BACKGROUND: Lerisetron, a competitive serotonin type 3 receptor (5-HT(3)R) antagonist, contains five functional groups capable of interacting with amino acids in the 5-HT(3)R binding site. Site directed mutagenesis studies of the 5-HT(3A)R have revealed several amino acids that are thought to form part of the binding domain of this receptor. The specific functional groups on the ligand that interact with these amino acids are, however, unknown. Using synthetic analogs of lerisetron as molecular probes in combination with site directed mutagenesis, we have identified some of these interactions and have proposed a model of the lerisetron binding site. RESULTS: Two analogs of lerisetron were synthesized to probe 5-HT(3)R functional group interactions with this compound. Analog 1 lacks the N1 benzyl group of lerisetron and analog 2 contains oxygen in place of the distal piperazine nitrogen. Both analogs show significantly decreased binding affinity to wildtype 5-HT(3AS)Rs. Mutations at W89, R91, Y142 and Y152 produced significant decreases in binding compared to wildtype receptors. Binding affinities of analogs 1 and 2 were altered only by mutations at W89, and Y152. CONCLUSIONS: Based on the data obtained for lerisetron and analogs 1 and 2, we have proposed a tentative model of the lerisetron binding pocket of the 5-HT(3AS)R. According to this model, The N-benzyl group interacts in a weak interaction with R91 while the benzimidazole group interacts with W89. Our data support an interaction of the distal amino nitrogen with Y142 and Y152. BioMed Central 2002-06-13 /pmc/articles/PMC116678/ /pubmed/12079499 http://dx.doi.org/10.1186/1471-2091-3-16 Text en Copyright © 2002 Venkataraman et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. |
spellingShingle | Research Article Venkataraman, Padmavati Joshi, Prasad Venkatachalan, Srinivasan P Muthalagi, Mani Parihar, Harish S Kirschbaum, Karen S Schulte, Marvin K Functional group interactions of a 5-HT(3)R antagonist |
title | Functional group interactions of a 5-HT(3)R antagonist |
title_full | Functional group interactions of a 5-HT(3)R antagonist |
title_fullStr | Functional group interactions of a 5-HT(3)R antagonist |
title_full_unstemmed | Functional group interactions of a 5-HT(3)R antagonist |
title_short | Functional group interactions of a 5-HT(3)R antagonist |
title_sort | functional group interactions of a 5-ht(3)r antagonist |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC116678/ https://www.ncbi.nlm.nih.gov/pubmed/12079499 http://dx.doi.org/10.1186/1471-2091-3-16 |
work_keys_str_mv | AT venkataramanpadmavati functionalgroupinteractionsofa5ht3rantagonist AT joshiprasad functionalgroupinteractionsofa5ht3rantagonist AT venkatachalansrinivasanp functionalgroupinteractionsofa5ht3rantagonist AT muthalagimani functionalgroupinteractionsofa5ht3rantagonist AT pariharharishs functionalgroupinteractionsofa5ht3rantagonist AT kirschbaumkarens functionalgroupinteractionsofa5ht3rantagonist AT schultemarvink functionalgroupinteractionsofa5ht3rantagonist |