Title:Molecular Modeling of Benzimidazole Derivatives: A Promising Series of GluN2B Selective NMDA Receptor Antagonists
Volume: 13
Issue: 2
Author(s): Marcos Vinicius Santana, Helena Carla Castro and Paula Alvarez Abreu*
Affiliation:
- Laboratorio de Modelagem Molecular e Pesquisa em Ciencias Farmaceuticas, Universidade Federal do Rio de Janeiro, Campus Macae, Macae,Brazil
Keywords:
NMDA receptor antagonists, benzimidazole derivatives, molecular modeling, structureactivity
relationship, docking, in silico analysis.
Abstract: Background: The N-methyl-D-aspartate receptors (NMDAR) are extremely important
ionotropic glutamate receptors in the central nervous system. These receptors are involved in different
pathological conditions, such as Parkinson's, Alzheimer's and Huntington's, and also in neuronal
death associated with trauma and stroke. Since the discovery of ifenprodil, many efforts have been
made to develop subunit specific NMDAR antagonists with fewer side effects, however without success
to deliver a marketed drug.
Objective: The aim of this work is to establish a structure-activity relationship analysis of a series of
benzimidazole derivatives described in the literature as GluN2B-selective antagonists and evaluate
their binding mode.
Method: Molecular modeling techniques were carried out, such as docking using Autodock Vina,
structure-activity relationship studies using Spartan program, in silico evaluation of the toxicological
profile and pharmacokinetic properties as intestinal absoption, blood-brain barrier permeation and
oral bioavailability.
Results: Our results showed that all compounds presented the structural features observed in ifenprodil-
like antagonists and that lipophilicity and number of hydrogen bond donors were the most
correlated descriptors with the biological activity. Our docking analysis also revealed a similar binding
mode in NMDAR. Furthermore, the benzimidazole derivatives with hydroxyl substituent showed
a good safety profile and good bioavailability according to Lipinski's Rule of Five and a modified
rule for central nervous system penetration, which could help in future optimizations.
Conclusion: In conclusion, our results indicate that benzimidazole derivatives could be useful
for the development of subunit selective NMDAR antagonists.
