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Molecules 2018, 23(5), 1128; https://doi.org/10.3390/molecules23051128

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

1
Instituto de Investigación en Ciencias Básicas y Aplicadas, Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Cuernavaca 62209, Morelos, Mexico
2
Departmento de Bioquímica, Escuela Superior de Medicina, Instituto Politécnico Nacional, Cd Mexico 11340, Mexico
3
Instituto de Investigación en Ciencias Básicas y Aplicadas, Centro de Investigación en Dinámica Celular, Universidad Autónoma del Estado de Morelos, Cuernavaca 62209, Morelos, Mexico
*
Author to whom correspondence should be addressed.
Academic Editor: Athina Geronikaki
Received: 14 March 2018 / Revised: 1 May 2018 / Accepted: 2 May 2018 / Published: 9 May 2018
(This article belongs to the Special Issue Recent Trends on Enzymes Inhibitors and Activators in Drug Research)
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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. View Full-Text
Keywords: heterocyclic GABA analogues; GABA-AT inhibitors; GABA-AT docking; molecular electrostatic potential heterocyclic GABA analogues; GABA-AT inhibitors; GABA-AT docking; molecular electrostatic potential
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Tovar-Gudiño, E.; Guevara-Salazar, J.A.; Bahena-Herrera, J.R.; Trujillo-Ferrara, J.G.; Martínez-Campos, Z.; Razo-Hernández, R.S.; Santiago, Á.; Pastor, N.; Fernández-Zertuche, M. Novel-Substituted Heterocyclic GABA Analogues. Enzymatic Activity against the GABA-AT Enzyme from Pseudomonas fluorescens and In Silico Molecular Modeling. Molecules 2018, 23, 1128.

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