Molecular Modeling of Benzimidazole Derivatives: A Promising Series of GluN2B Selective NMDA Receptor Antagonists

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.