Exploring the bioactive constituents from spices targeting N-methyl-d-aspartate receptors: An in silico and in vitro approach to identify druggable leads against neurological disability

Abstract

N-methyl-d-aspartate (NMDA) receptors are validated druggable targets for the treatment of Alzheimer's and other associated neurological conditions, particularly in individuals with disabilities. Considering the excitotoxicity associated with NMDA receptors, which leads to neuronal damage, cognitive impairment, and limitations of current therapeutic regimens, better therapeutic candidates are required. One of the validated drug discovery approaches is computer-assisted drug discovery, supplemented by molecular docking, mechanics, and dynamics. To this end, we curated 134 bioactive constituents derived from spices. These were subjected to high-throughput virtual screening (HTVS) considering the pharmacophoric features of the NMDA receptor. Molecular docking, followed by molecular mechanics and dynamics, indicated that curcumin and quercetin could plausibly bind to the NMDA receptor in comparison to memantine. In vitro ELISA-based analysis revealed that curcumin may inhibit the NMDA receptor with an IC50 of 2.36 μM compared to memantine's 736.48 nM, employed as a positive control. However, targeting the neuronal receptor NMDA requires that the ligand efficiently cross the blood-brain barrier (BBB). To overcome this challenge, we performed a rational bioisosteric replacement strategy to potentially optimize the pharmacokinetic features of curcumin without affecting its NMDA binding. We generated 150 bioisosteres of curcumin, and through extensive computational analyses, the top 5 scoring molecules were further validated via a molecular dynamics approach. However advantageous, in the present work, curcumin or its proposed derivatives have not been corroborated by extensive biological investigation. It is a prototype study to identify the druggable leads from the spices that have the potency to interact and inhibit NMDA. Owing to this, the mechanism of action is not fully elucidated. Further, the work upon validation (biologically) may serve as a useful pharmacophore (tool molecule) using which NMDA may be downregulated. The designed derivatives thus open avenues to synthesize and biologically test them against NMDA inhibition, plausibly establishing their roles in Alzheimer's and related disabilities.