Structure-Based Virtual Screening to Identify Negative Allosteric Modulators of NMDA

Abstract

BACKGROUND: NMDA(N-methyl-D-aspartate) Receptor is one of the ionotropic receptor sub types of Glutamate, the most abundant excitatory neurotransmitter in Human Brain. Besides physiological roles in learning and memory, neuronal plasticity and somatosensory function NMDA-R overstimulation is also implicated in a pathophysiological mechanism of 'excitotoxicity'. In this study, an allosteric site has been focused for designing inhibitors of the most abundant form of this receptor of utility in many acute (stroke, traumatic brain injury) and chronic neurodegenerative diseases such as Parkinson's disease, Huntington's, Alzheimer's, and others. METHODS: Targeting this specific site at the interdimer interface of ligand binding domain of GluN2A containing NMDA-Rs and using pharmacophore based virtual screening, docking, computational ADME prediction techniques and MD simulation studies, blood brain barrier permeable potentially therapeutic compounds as opposed to only pharmacological tools currently available were sought. RESULTS: Proceeding through the in-silico methodology, the study was successful at reaching to 5 compounds from ChEMBL Database which were predicted to be potential NMDA inhibitor drugs. CONCLUSION: The product of the study are compounds which have been validated through pharmacophore and score-based screening and MD simulation techniques to be allosterically inhibiting NMDA receptors and with favorable pharmacokinetic profile are likely to be therapeutic agents ready for in-vitro and in-vivo testing.