Poblado C-11 José María Morelos y Pavón, Mexico
Poblado C-11 José María Morelos y Pavón, Mexico

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Matus J.S.M.,University of Veracruz | Morales F.R.R.,University of Veracruz | Basurto J.C.,Laboratorio Of Modelado Molecular | Sanchez J.S.C.,University of Veracruz | And 2 more authors.
Acta Bioquimica Clinica Latinoamericana | Year: 2010

Epilepsy is de3ned as a chronic condition produced by different etiologies, characterized by the repetition of crises due to an excessive discharge of the cerebral neurons associated with clinical symptoms. It responds to a fast ion depolarization in a population of abnormal neurons. Causes of epilepsy are: genetic alterations, perinatal anoxia, traumatisms, tumors, congenital malformations, metabolic alterations, drug poisonings, and infections of the nervous system. Epileptic seizure is the transitory occurrence of signs and abnormal symptoms caused by excessive or synchronous neuronal activity, whereas, epilepsy is characterized by a permanent predisposition to generate seizures. During depolarization of neuronal membrane, calcium ions play an important role because they are intracellular messengers that regulate functions like: neurotransmitter release, neurosecretion, neuronal excitation, neuron survival and gene expression regulation . The in4ux of calcium through the plasmatic membrane represents a way to control intracellular calcium level. The mechanism of the entrance of calcium to the neuron is little known, but understanding the structure, function and regulation of voltagegated calcium channels is of remarkable progress.


Saavedra-Velez M.V.,Laboratorio Of Modelado Molecular | Saavedra-Velez M.V.,University of Veracruz | Correa-Basurto J.,Laboratorio Of Modelado Molecular | Matus M.H.,University of Veracruz | And 6 more authors.
Journal of Computer-Aided Molecular Design | Year: 2014

The aim of this study was to identify compounds that possess anticonvulsant activity by using a pentylenetetrazol (PTZ)-induced seizure model. Theoretical studies of a set of ligands, explored the binding affinities of the ligands for the GABAA receptor (GABAAR), including some benzodiazepines. The ligands satisfy the Lipinski rules and contain a pharmacophore core that has been previously reported to be a GABAAR activator. To select the ligands with the best physicochemical properties, all of the compounds were analyzed by quantum mechanics and the energies of the highest occupied molecular orbital and lowest unoccupied molecular orbital were determined. Docking calculations between the ligands and the GABAAR were used to identify the complexes with the highest Gibbs binding energies. The identified compound D1 (dibenzo(b,f)(1,4)diazocine-6,11(5H,12H)-dione) was synthesized, experimentally tested, and the GABAAR-D1 complex was submitted to 12-ns-long molecular dynamics (MD) simulations to corroborate the binding conformation obtained by docking techniques. MD simulations were also used to analyze the decomposition of the Gibbs binding energy of the residues involved in the stabilization of the complex. To validate our theoretical results, molecular docking and MD simulations were also performed for three reference compounds that are currently in commercial use: clonazepam (CLZ), zolpidem and eszopiclone. The theoretical results show that the GABAAR-D1, and GABAAR-CLZ complexes bind to the benzodiazepine binding site, share a similar map of binding residues, and have similar Gibbs binding energies and entropic components. Experimental studies using a PTZ-induced seizure model showed that D1 possesses similar activity to CLZ, which corroborates the predicted binding free energy identified by theoretical calculations. © 2014 Springer International Publishing Switzerland.


Durand-Niconoff J.S.,University of Veracruz | Cruz-Kuri L.,University of Veracruz | Matus M.H.,University of Veracruz | Correa-Basurto J.,Laboratorio Of Modelado Molecular | And 2 more authors.
Journal of Chemical Sciences | Year: 2011

The possible correlation between Hammett's constant (σp), a characteristic parameter of functional groups with electrodonating or electroaccepting properties, and two indices of global reactivity were calculated in the gas phase. Parameters associated to a set of 22 structural variants of isatoic anhydride (2H-3, 1-benzoxazin-2,4(1H)-dione, ISA), replaced with diverse functional groups, were explored applying linear and quadratic statistical models for numerical analysis of the results. © Indian Academy of Sciences.


PubMed | Laboratorio Of Modelado Molecular
Type: Journal Article | Journal: Journal of computer-aided molecular design | Year: 2014

The aim of this study was to identify compounds that possess anticonvulsant activity by using a pentylenetetrazol (PTZ)-induced seizure model. Theoretical studies of a set of ligands, explored the binding affinities of the ligands for the GABA(A) receptor (GABA(A)R), including some benzodiazepines. The ligands satisfy the Lipinski rules and contain a pharmacophore core that has been previously reported to be a GABA(A)R activator. To select the ligands with the best physicochemical properties, all of the compounds were analyzed by quantum mechanics and the energies of the highest occupied molecular orbital and lowest unoccupied molecular orbital were determined. Docking calculations between the ligands and the GABA(A)R were used to identify the complexes with the highest Gibbs binding energies. The identified compound D1 (dibenzo(b,f)(1,4)diazocine-6,11(5H,12H)-dione) was synthesized, experimentally tested, and the GABA(A)R-D1 complex was submitted to 12-ns-long molecular dynamics (MD) simulations to corroborate the binding conformation obtained by docking techniques. MD simulations were also used to analyze the decomposition of the Gibbs binding energy of the residues involved in the stabilization of the complex. To validate our theoretical results, molecular docking and MD simulations were also performed for three reference compounds that are currently in commercial use: clonazepam (CLZ), zolpidem and eszopiclone. The theoretical results show that the GABA(A)R-D1, and GABA(A)R-CLZ complexes bind to the benzodiazepine binding site, share a similar map of binding residues, and have similar Gibbs binding energies and entropic components. Experimental studies using a PTZ-induced seizure model showed that D1 possesses similar activity to CLZ, which corroborates the predicted binding free energy identified by theoretical calculations.

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