Abstract
Over-activation of extra-synaptic NMDARs by excessive glutamate is known to cause excitotoxicity. The molecular mechanism of how this excitotoxicity occurs was revealed recently. This paper presents the results of in silico studies aimed at finding potential small-molecule inhibitors that can block this mechanism, namely the extra-synaptic NMDAR/TRPM4 interaction. We screened for small molecules according to 2D (at least Tanimoto threshold was 90%) and/or 3D similarity, molecular weight, lipophilicity using control compounds (C8 and C19) targeting this interaction. We then pre-filtered these molecules according to their drug-likeness and toxicity profiles. After pre-filtering, we performed a docking study against the extra-synaptic NMDAR/TRPM4 interaction with the remaining 26 compounds. In addition, we determined that selected compounds exhibit low affinity for classical NMDAR ligand binding sites. Ultimately, we identified four novel compounds (C8-12, C8-15, C19-3, C19-4) that could block the extra-synaptic NMDAR/TRPM4 interaction without inhibiting the normal function of synaptic NMDARs.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
