6-Imino-2-thioxo-pyrimidinones as a new class of dipeptidyl peptidase IV inhibitors

被引：0
作者：
Dubravko Jelić
Krunoslav Nujić
Višnja Stepanić
Krunoslav Kovačević
Donatella Verbanac
机构：
[1] GlaxoSmithKline Research Center Zagreb Ltd.,Department for Molecular Medicine
[2] Ruđer Bošković Institute,undefined
[3] University of Zagreb,undefined
[4] School of Medicine,undefined
[5] Center for Translational and Clinical Research,undefined
来源：
Medicinal Chemistry Research | 2011年 / 20卷
关键词：
DPP IV inhibitor; Pyrimidinone; Enzyme kinetics; Molecular docking; Cytotoxicity;
D O I：
暂无
中图分类号：
学科分类号：
摘要：
Dipeptidyl peptidase IV is a glycoprotein which removes N-terminal dipeptides from physiologically relevant polypeptides. An homologous series of 6-imino-2-thioxo-5-{[3,4,5-tris(methyloxy)phenyl]methyl}-2,5-dihydro-4(3H)-pyrimidinones has been tested for inhibition of DPP IV activity. The inhibitory effects at 0.1 mM were observed. Enzyme kinetic studies revealed that compounds inhibit DPP IV activity competitively. According to the molecular docking analysis, the inhibitors are anchored into the DPP IV hydrolytic site by interactions of the pyrimidinone core with Glu206, Tyr662, and Tyr547, with the alkyl chain entering the S1 pocket. We conclude that pyrimidinone-like compounds are a promising new scaffold for reversible inhibition of DPP IV.
引用
收藏
页码：339 / 345
页数：6
相关论文
共 173 条
[1]  
Abbott CA(1999)Two highly conserved glutamic acid residues in the predicted beta propeller domain of dipeptidyl peptidase IV are required for its enzyme activity FEBS Lett 458 278-284
[2]  
McCaughan GW(2000)Cloning, expression and chromosomal localization of a novel human dipeptidyl peptidase (DPP) IV homolog, DPP8 Eur J Biochem 267 6140-6150
[3]  
Gorrell MD(1979)Controlled synthesis of HBsAg in a differentiated human liver carcinoma-derived cell line Nature 282 615-616
[4]  
Abbott CA(2004)Crystal structure of human dipeptidyl peptidase IV in complex with a decapeptide reveals details on substrate specificity and tetrahedral intermediate formation Protein Sci 13 412-421
[5]  
Yu DMT(1998)Flexible docking using TABU search and an empirical estimate of binding affinity Proteins 33 367-382
[6]  
Woollatt E(2003)Announcing the worldwide Protein Data Bank Nat Struct Biol 10 980-542
[7]  
Sutherland GR(1977)The Protein Data Bank: a computer-based archival file for macromolecular structures J Mol Biol 112 535-73
[8]  
McCaughan GW(2003)The multifunctional or moonlighting protein CD26/DPPIV Eur J Cell Biol 82 53-101
[9]  
Gorrell MD(2000)Development of a tertiary-structure model of the C-terminal domain of DPP IV Adv Exp Med Biol 477 97-4766
[10]  
Aden DP(2004)Substituted piperazines as novel dipeptidyl peptidase IV inhibitors Bioorg Med Chem Lett 14 4763-31
12345678910