title: Molecular dynamics and free energy studies of chirality specificity effects on aminobenzo[a]quinolizine inhibitors binding to DPP-IV.
abstract: 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.
authors.affiliation: College of Chemistry and Chemical Engineering, Graduate University of the Chinese Academy of Sciences, Beijing 100049, People's Republic of China.
authors.forename: Cui
authors.initials: C
authors.lastname: Wei
authors.forename: Liang
authors.initials: L
authors.lastname: Desheng
authors.forename: Gao
authors.initials: G
authors.lastname: Jian
authors.forename: Luo
authors.initials: L
authors.lastname: Fang
authors.forename: Geng
authors.initials: G
authors.lastname: Lingling
authors.forename: Ji
authors.initials: J
authors.lastname: Mingjuan
mesh_terms: D062365:Aminobenzoates / Q000737:chemistry / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D011807:Quinolizines / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D062365:Aminobenzoates; D054873:Dipeptidyl-Peptidase IV Inhibitors; D011807:Quinolizines; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4