TY - JOUR
T1 - Seeking potential anticonvulsant agents that target GABAA receptors using experimental and theoretical procedures
AU - Saavedra-Vélez, Margarita Virginia
AU - Correa-Basurto, José
AU - Matus, Myrna H.
AU - Gasca-Pérez, Eloy
AU - Bello, Martiniano
AU - Cuevas-Hernández, Roberto
AU - García-Rodríguez, Rosa Virginia
AU - Trujillo-Ferrara, José
AU - Ramos-Morales, Fernando Rafael
N1 - Publisher Copyright:
© 2014 Springer International Publishing Switzerland.
PY - 2014/12
Y1 - 2014/12
N2 - 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.
AB - 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.
KW - Docking
KW - GABAR
KW - MD simulations
KW - Synthesis
UR - http://www.scopus.com/inward/record.url?scp=84922089043&partnerID=8YFLogxK
U2 - 10.1007/s10822-014-9798-z
DO - 10.1007/s10822-014-9798-z
M3 - Artículo
C2 - 25298123
SN - 0920-654X
VL - 28
SP - 1217
EP - 1232
JO - Journal of Computer-Aided Molecular Design
JF - Journal of Computer-Aided Molecular Design
IS - 12
ER -