Back to Search
Start Over
Paralog-divergent Features May Help Reduce Off-target Effects of Drugs: Hints from Glucagon Subfamily Analysis.
- Source :
-
Genomics, proteomics & bioinformatics [Genomics Proteomics Bioinformatics] 2017 Aug; Vol. 15 (4), pp. 246-254. Date of Electronic Publication: 2017 Jun 20. - Publication Year :
- 2017
-
Abstract
- 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.<br /> (Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)
- Subjects :
- Amino Acid Sequence
Animals
Binding Sites
Diabetes Mellitus, Type 2
Glucagon-Like Peptide-1 Receptor antagonists & inhibitors
Glucagon-Like Peptide-1 Receptor classification
Humans
Molecular Dynamics Simulation
Pharmaceutical Preparations chemistry
Phylogeny
Protein Structure, Tertiary
Pyrazoles chemistry
Pyrazoles metabolism
Receptors, Glucagon antagonists & inhibitors
Receptors, Glucagon classification
Sequence Alignment
beta-Alanine analogs & derivatives
beta-Alanine chemistry
beta-Alanine metabolism
Glucagon-Like Peptide-1 Receptor metabolism
Pharmaceutical Preparations metabolism
Receptors, Glucagon metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2210-3244
- Volume :
- 15
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Genomics, proteomics & bioinformatics
- Publication Type :
- Academic Journal
- Accession number :
- 28642113
- Full Text :
- https://doi.org/10.1016/j.gpb.2017.03.004