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

• Published in: Genomics, proteomics & bioinformatics proteomics & bioinformatics, 2017-08, Vol.15 (4), p.246-254
• Main Authors: Sa, Zhining, Zhou, Jingqi, Zou, Yangyun, Su, Zhixi, Gu, Xun
• Format: Article
• Language: English
• Subjects: Drug specificity; Evolutionary conservation; Functional divergence; Functional site; G蛋白偶联受体; Original Research; Paralog; 亚科; 发散; 同源蛋白; 氨基酸类; 特征; 胰高血糖素样肽-1; 靶向药物
• ISSN: 1672-0229; 2210-3244
• DOI: 10.1016/j.gpb.2017.03.004

Side effects from targeted drugs remain a serious conccrn. One reason is the nonselective binding of a drug to unintended proteins such as its paralogs, which arc highly homologous in sequences and have similar structures and drug-binding pockets. To identify targctablc differences between paralogs, we analyzed two types （type-I and type-ll） 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-I receptor （GLP-I R）, exhibit divergence in ligands and are clinically validated drug targets for type 2 diabetes. Our data showed that type-ll alnino 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-IR. The divergent features between GCGR and GLP-I R 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.