Molecular level activation insights from a NR2A/NR2B agonist

AbstractN-methyl D-aspartate receptors (NMDARs), a subclass of glutamate receptors have broad actions in neural transmission for major brain functions. Overactivation of NMDARs leading to “excitotoxicity” is the underlying mechanism of neuronal death in a number of neurological diseases, especially stroke. Much research effort has been directed toward developing pharmacological agents to modulate NMDAR actions for treating neurological diseases, in particular stroke. Here, we report that Alliin, a sulfoxide in fresh garlic, exhibits affinity toward NR2A as well as NR2B receptors based on virtual screening. Biological activities of Alliin on these two receptors were confirmed in electrophysiological studies. Ligand-binding site closure, a structural change precluding ion channel opening, was observed with Alliin during 100 ns molecular dynamics simulation. Alliin interactions with NR2A and NR2B suggest that residues E/A413, H485, T690, and Y730 may play important roles in the conformation shift. Activation of NR2A and NR2B by Alliin can be differentiated from that caused by glutamate, the endogenous neurotransmitter. These characteristic molecular features in NR2A and NR2B activation provide insight into structural requirements for future development of novel drugs with selective interaction with NR2A and NR2B for treating neurological diseases, particularly stroke.Keywords: Alliintraditional Chinese medicine (TCM)molecular dynamics (MD)N-methyl D-aspartate receptors (NMDAR) AcknowledgmentsThe research was supported by grants from the National Science Council of Taiwan (NSC101-2325-B-039-001), Asia University (100-asia-56, asia100-cmu-2, 101-asia-59), China Medical University (DMR-101-094, DMR-102-105), and China Medical University Hospital (DMR-102-001, DMR-102-003, DMR-102-051). This study is also supported in part by Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH102-TD-B-111-004) and Taiwan Department of Health Cancer Research Center of Excellence (DOH102-TD-C-111-005). We are grateful to Asia University and the National Center of High-performance Computing for computer time and facilities.