Molecular dynamics and free energy studies of chirality specificity effects on aminobenzo[a]quinolizine inhibitors binding to DPP-IV

被引:4
|
作者
Cui Wei [1 ]
Liang Desheng [1 ]
Gao Jian [1 ]
Luo Fang [1 ]
Geng Lingling [1 ]
Ji Mingjuan [1 ]
机构
[1] Chinese Acad Sci, Grad Univ, Coll Chem & Chem Engn, Beijing 100049, Peoples R China
基金
美国国家科学基金会;
关键词
Aminobenzo[a]quinolizine inhibitors; Chirality specificity; DPP-IV; MM/GBSA; Molecular dynamics simulations; DIPEPTIDYL PEPTIDASE-IV; GLUCAGON-LIKE PEPTIDE-1; CONTINUUM MODELS; FORCE-FIELD; POTENT; MECHANICS; SIMULATIONS; SITAGLIPTIN; AFFINITIES; ALOGLIPTIN;
D O I
10.1007/s00894-012-1653-3
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The aminobenzo[a]quinolizines were investigated as a novel class of DPP-IV inhibitors. The stereochemistry of this class plays an important role in the bioactivity. In this study, the mechanisms of how different configuration of three chiral centers of this class influences the binding affinity were investigated by molecular dynamics simulations, free energy decomposition analysis. The S configuration for chiral center 3* is decisive for isomers to maintain high bioactivity; the chirality effect of chiral center 2* on the binding affinity is largely dependent, while the S configuration for chiral center 2* is preferable to R configuration for the bioactivity gain; the effect of chiral center 11b* on the binding affinity is insignificant. The chirality specificity for three chiral centers is responsible for distinction of two van der Waals contacts with Tyr547 and Phe357, and of H-bonding interactions with Arg125 and Glu206. Particularly, the Arg125 to act as a bridge in the H-bonding network contributes to stable H-bonding interactions of isomer in DPP-IV active site.
引用
收藏
页码:1167 / 1177
页数:11
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