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

作　　者：Zhining Sa Jingqi Zhou Yangyun Zou Zhixi Su Xun Gu 

机构地区：[1]State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology,School of Life,Sciences,Fudan University,Shanghai 200433,China [2]Department of Genetics,Development and Cell Biology,Program of Bioinformatics and Computational Biology,Iowa State University,Ames,IA 50011,USA

出　　处：《Genomics, Proteomics & Bioinformatics》2017年第4期246-254,共9页基因组蛋白质组与生物信息学报（英文版）

基　　金：supported by a grant from the National Natural Science Foundation of China(Grant No.31571355 and 31301034);supported by Fudan University,China;Iowa State University,United States

摘　　要：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.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.

关 键 词：PARALOG Functional divergence Functional site Drug specificity Evolutionary conservation 

分 类 号：R96[医药卫生—药理学]