Exploring the binding mechanisms of diaminopimelic acid analogs to meso-diaminopimelate dehydrogenase by molecular modeling

J Mol Graph Model. 2018 Aug:83:100-111. doi: 10.1016/j.jmgm.2018.05.011. Epub 2018 Jun 2.

Abstract

Meso-Diaminopimelic acid (meso-2,6-diamino-heptanedioic acid, DAP) is an important component of the cell wall of many bacteria. Meso-diaminopimelate dehydrogenase (m-Ddh) is a critical enzyme in the process of converting tetrahydrodipicolinate to DAP. Here, we are proposing that DAP analogs targeting m-Ddh may be considered as potential antibiotics. Four DAP analogs without significant structural change from DAP have been obtained and their inhibitory potencies against m-Ddh from the P. gingivalis strain W83 show significant differences from that of DAP. However, their inhibitory mechanisms as for how simple structural change influences the inhibitory potency remain unknown. Therefore, we employed molecular modeling methods to obtain insight into the inhibitory mechanisms of DAP and analogs with m-Ddh. The predicted binding mode of DAP was highly consistent with the experimental structural data and disclosed the important roles played by the binding pocket residues. According to our predictions, the isoxazoline ring of compounds 1 and 2 and the double bonds in compounds 3 and 4 had distinct influences on these compounds' binding to m-Ddh. This enriched understanding of the inhibitory mechanisms of DAP and these four analogs to m-Ddh has provided new and relevant information for future rational development of potent inhibitors targeting m-Ddh.

Keywords: Antibiotics; Binding mode; Diaminopimelic acid (DAP) analogs; Meso-diaminopimelate dehydrogenase (m-Ddh); Molecular dynamics simulations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Oxidoreductases / chemistry*
  • Amino Acid Oxidoreductases / metabolism
  • Biosynthetic Pathways
  • Diaminopimelic Acid / analogs & derivatives
  • Diaminopimelic Acid / chemistry*
  • Diaminopimelic Acid / metabolism
  • Hydrogen Bonding
  • Molecular Conformation
  • Molecular Docking Simulation*
  • Molecular Dynamics Simulation*
  • Molecular Structure
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Diaminopimelic Acid
  • Amino Acid Oxidoreductases
  • diaminopimelate dehydrogenase