TY - JOUR
T1 - QSAR and molecular docking studies of the inhibitory activity of novel heterocyclic GABA analogues over GABA-AT
AU - Rodríguez-Lozada, Josué
AU - Tovar-Gudiño, Erika
AU - Guevara-Salazar, Juan Alberto
AU - Razo-Hernández, Rodrigo Said
AU - Santiago, Ángel
AU - Pastor, Nina
AU - Fernández-Zertuche, Mario
N1 - Publisher Copyright:
© 2018 by the authors.
PY - 2018/11/15
Y1 - 2018/11/15
N2 - 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.
AB - 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.
KW - GABA-AT docking
KW - GABA-AT enzyme
KW - Heterocyclic GABA analogues
KW - Inhibitors
KW - QSAR
UR - http://www.scopus.com/inward/record.url?scp=85056642425&partnerID=8YFLogxK
U2 - 10.3390/molecules23112984
DO - 10.3390/molecules23112984
M3 - Artículo
C2 - 30445747
AN - SCOPUS:85056642425
VL - 23
JO - Molecules
JF - Molecules
IS - 11
M1 - 2984
ER -