Journal of Molecular Modeling

, Volume 19, Issue 3, pp 1167–1177

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

Authors

  • Cui Wei
    • College of Chemistry and Chemical EngineeringGraduate University of the Chinese Academy of Sciences
  • Liang Desheng
    • College of Chemistry and Chemical EngineeringGraduate University of the Chinese Academy of Sciences
  • Gao Jian
    • College of Chemistry and Chemical EngineeringGraduate University of the Chinese Academy of Sciences
  • Luo Fang
    • College of Chemistry and Chemical EngineeringGraduate University of the Chinese Academy of Sciences
  • Geng Lingling
    • College of Chemistry and Chemical EngineeringGraduate University of the Chinese Academy of Sciences
    • College of Chemistry and Chemical EngineeringGraduate University of the Chinese Academy of Sciences
Original Paper

DOI: 10.1007/s00894-012-1653-3

Cite this article as:
Wei, C., Desheng, L., Jian, G. et al. J Mol Model (2013) 19: 1167. doi:10.1007/s00894-012-1653-3

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.

https://static-content.springer.com/image/art%3A10.1007%2Fs00894-012-1653-3/MediaObjects/894_2012_1653_Figa_HTML.gif
Figure

The S configuration for chiral center 3* is decisive for high bioactivity; the chirality effect of chiral center 2* on binding affinity is largely dependent, while the S configuration for 2* is preferable to R for bioactivity gain; the chirality specificity for chiral center 11b* to binding affinity is insignificant.

Keywords

Aminobenzo[a]quinolizine inhibitorsChirality specificityDPP-IVMM/GBSAMolecular dynamics simulations

Supplementary material

894_2012_1653_MOESM1_ESM.doc (272 kb)
ESM 1(DOC 272 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2012