Background The N-methyl-D-aspartate (NMDA) receptors are glutamate receptors that play vital roles in central nervous system development and are involved in synaptic plasticity, which is an essential process for learning and memory. The subunit N-methyl D-aspartate receptor subtype 2B (NR2B) is the chief excitatory neurotransmitter receptor in the mammalian brain. Disturbances in the neurotransmission mediated by the NMDA receptor are caused by its overexposure to glutamate neurotransmitter and can be treated by its binding to an antagonist. Among several antagonists, conantokins from cone snails are reported to bind to NMDA receptors. Methods This study was designed to analyze the binding mode of conantokins with NMDA receptors in both humans and rats. To study interactions, dockings were performed using AutoDock 4.2 and their results were further analyzed using various computational tools. Results Detailed analyses revealed that these ligands can bind to active site residues of both receptors as reported in previous studies. Conclusions In light of the present results, we suggest that these conantokins can act as antagonists of those receptors and play an important role in understanding the importance of inhibition of NMDA receptors for treatment of Alzheimer's disease.(AU)