Novel-Substituted Heterocyclic GABA Analogues. Enzymatic Activity against the GABA-AT Enzyme from Pseudomonas fluorescens and In Silico Molecular Modeling

Molecules. 2018 May 9;23(5):1128. doi: 10.3390/molecules23051128.

Abstract

γ-Aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in the central nervous system, and a deficiency of GABA is associated with serious neurological disorders. Due to its low lipophilicity, there has been an intensive search for new molecules with increased lipophilicity to cross the blood-brain barrier to raise GABA concentrations. We have designed and evaluated in vitro and in silico some new analogues of GABA, where the nitrogen atom at the γ-position is embedded in heterocyclic scaffolds and determined their inhibitory potential over the GABA-AT enzyme from Pseudomonas fluorescens. These modifications lead to compounds with inhibitory activity as it occurs with compounds 18a and 19a. The construction of Pseudomonas fluorescens and human GABA-AT models were carried out by homology modeling. Docking assays were done for these compounds over the GABA-AT enzyme models where 19a showed a strong interaction with both GABA-AT enzymes.

Keywords: GABA-AT docking; GABA-AT inhibitors; heterocyclic GABA analogues; molecular electrostatic potential.

MeSH terms

  • 4-Aminobutyrate Transaminase / antagonists & inhibitors*
  • Catalytic Domain
  • Computer Simulation*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / chemistry*
  • Heterocyclic Compounds / pharmacology*
  • Humans
  • Hydrogen Bonding
  • Models, Molecular*
  • Molecular Docking Simulation
  • Pseudomonas fluorescens / enzymology*
  • Static Electricity
  • gamma-Aminobutyric Acid / analogs & derivatives*

Substances

  • Enzyme Inhibitors
  • Heterocyclic Compounds
  • gamma-Aminobutyric Acid
  • 4-Aminobutyrate Transaminase