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Open AccessArticle

QSAR and Molecular Docking Studies of the Inhibitory Activity of Novel Heterocyclic GABA Analogues over GABA-AT

1
Instituto de Investigación en Ciencias Básicas y Aplicadas, Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, 62209 Cuernavaca, Morelos, Mexico
2
Departmento de Bioquímica, Escuela Superior de Medicina, Instituto Politécnico Nacional, 11340 Cd México, Mexico
3
Instituto de Investigación en Ciencias Básicas y Aplicadas, Centro de Investigación en Dinámica Celular, Universidad Autónoma del Estado de Morelos, 62209 Cuernavaca, Morelos, Mexico
*
Author to whom correspondence should be addressed.
Molecules 2018, 23(11), 2984; https://doi.org/10.3390/molecules23112984
Received: 12 September 2018 / Revised: 9 November 2018 / Accepted: 9 November 2018 / Published: 15 November 2018
(This article belongs to the Special Issue QSAR and QSPR: Recent Developments and Applications)
We have previously reported the synthesis, in vitro and in silico activities of new GABA analogues as inhibitors of the GABA-AT enzyme from Pseudomonas fluorescens, where the nitrogen atom at the γ-position is embedded in heterocyclic scaffolds. With the goal of finding more potent inhibitors, we now report the synthesis of a new set of GABA analogues with a broader variation of heterocyclic scaffolds at the γ-position such as thiazolidines, methyl-substituted piperidines, morpholine and thiomorpholine and determined their inhibitory potential over the GABA-AT enzyme from Pseudomonas fluorescens. These structural modifications led to compound 9b which showed a 73% inhibition against this enzyme. In vivo studies with PTZ-induced seizures on male CD1 mice show that compound 9b has a neuroprotective effect at a 0.50 mmole/kg dose. A QSAR study was carried out to find the molecular descriptors associated with the structural changes in the GABA scaffold to explain their inhibitory activity against GABA-AT. Employing 3D molecular descriptors allowed us to propose the GABA analogues enantiomeric active form. To evaluate the interaction with Pseudomonas fluorescens and human GABA-AT by molecular docking, the constructions of homology models was carried out. From these calculations, 9b showed a strong interaction with both GABA-AT enzymes in agreement with experimental results and the QSAR model, which indicates that bulky ligands tend to be the better inhibitors especially those with a sulfur atom on their structure. View Full-Text
Keywords: heterocyclic GABA analogues; GABA-AT enzyme; QSAR; GABA-AT docking; inhibitors heterocyclic GABA analogues; GABA-AT enzyme; QSAR; GABA-AT docking; inhibitors
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Rodríguez-Lozada, J.; Tovar-Gudiño, E.; Guevara-Salazar, J.A.; Razo-Hernández, R.S.; Santiago, Á.; Pastor, N.; Fernández-Zertuche, M. QSAR and Molecular Docking Studies of the Inhibitory Activity of Novel Heterocyclic GABA Analogues over GABA-AT. Molecules 2018, 23, 2984.

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