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Paralog-divergent Features May Help Reduce Off-target Effects of Drugs: Hints from Glucagon Subfamily Analysis

Side effects from targeted drugs remain a serious concern. One reason is the nonselective binding of a drug to unintended proteins such as its paralogs, which are highly homologous in sequences and have similar structures and drug-binding pockets. To identify targetable differences between paralogs,...

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Autores principales: Sa, Zhining, Zhou, Jingqi, Zou, Yangyun, Su, Zhixi, Gu, Xun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582795/
https://www.ncbi.nlm.nih.gov/pubmed/28642113
http://dx.doi.org/10.1016/j.gpb.2017.03.004
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author Sa, Zhining
Zhou, Jingqi
Zou, Yangyun
Su, Zhixi
Gu, Xun
author_facet Sa, Zhining
Zhou, Jingqi
Zou, Yangyun
Su, Zhixi
Gu, Xun
author_sort Sa, Zhining
collection PubMed
description Side effects from targeted drugs remain a serious concern. One reason is the nonselective binding of a drug to unintended proteins such as its paralogs, which are highly homologous in sequences and have similar structures and drug-binding pockets. To identify targetable differences between paralogs, we analyzed two types (type-I and type-II) of functional divergence between two paralogs in the known target protein receptor family G-protein coupled receptors (GPCRs) at the amino acid level. Paralogous protein receptors in glucagon-like subfamily, glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), exhibit divergence in ligands and are clinically validated drug targets for type 2 diabetes. Our data showed that type-II amino acids were significantly enriched in the binding sites of antagonist MK-0893 to GCGR, which had a radical shift in physicochemical properties between GCGR and GLP-1R. We also examined the role of type-I amino acids between GCGR and GLP-1R. The divergent features between GCGR and GLP-1R paralogs may be helpful in their discrimination, thus enabling the identification of binding sites to reduce undesirable side effects and increase the target specificity of drugs.
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spelling pubmed-55827952017-09-14 Paralog-divergent Features May Help Reduce Off-target Effects of Drugs: Hints from Glucagon Subfamily Analysis Sa, Zhining Zhou, Jingqi Zou, Yangyun Su, Zhixi Gu, Xun Genomics Proteomics Bioinformatics Original Research Side effects from targeted drugs remain a serious concern. One reason is the nonselective binding of a drug to unintended proteins such as its paralogs, which are highly homologous in sequences and have similar structures and drug-binding pockets. To identify targetable differences between paralogs, we analyzed two types (type-I and type-II) of functional divergence between two paralogs in the known target protein receptor family G-protein coupled receptors (GPCRs) at the amino acid level. Paralogous protein receptors in glucagon-like subfamily, glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), exhibit divergence in ligands and are clinically validated drug targets for type 2 diabetes. Our data showed that type-II amino acids were significantly enriched in the binding sites of antagonist MK-0893 to GCGR, which had a radical shift in physicochemical properties between GCGR and GLP-1R. We also examined the role of type-I amino acids between GCGR and GLP-1R. The divergent features between GCGR and GLP-1R paralogs may be helpful in their discrimination, thus enabling the identification of binding sites to reduce undesirable side effects and increase the target specificity of drugs. Elsevier 2017-08 2017-06-20 /pmc/articles/PMC5582795/ /pubmed/28642113 http://dx.doi.org/10.1016/j.gpb.2017.03.004 Text en © 2017 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Original Research
Sa, Zhining
Zhou, Jingqi
Zou, Yangyun
Su, Zhixi
Gu, Xun
Paralog-divergent Features May Help Reduce Off-target Effects of Drugs: Hints from Glucagon Subfamily Analysis
title Paralog-divergent Features May Help Reduce Off-target Effects of Drugs: Hints from Glucagon Subfamily Analysis
title_full Paralog-divergent Features May Help Reduce Off-target Effects of Drugs: Hints from Glucagon Subfamily Analysis
title_fullStr Paralog-divergent Features May Help Reduce Off-target Effects of Drugs: Hints from Glucagon Subfamily Analysis
title_full_unstemmed Paralog-divergent Features May Help Reduce Off-target Effects of Drugs: Hints from Glucagon Subfamily Analysis
title_short Paralog-divergent Features May Help Reduce Off-target Effects of Drugs: Hints from Glucagon Subfamily Analysis
title_sort paralog-divergent features may help reduce off-target effects of drugs: hints from glucagon subfamily analysis
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582795/
https://www.ncbi.nlm.nih.gov/pubmed/28642113
http://dx.doi.org/10.1016/j.gpb.2017.03.004
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