COMPUTATIONAL IDENTIFICATION OF NOVELNMDARECEPTORANTAGONISTS AS THERAPEUTICCANDIDATESFOR ALZHEIMER'SDISEASE

Abstract

NMDA receptors are ionotropic glutamate receptors that are involved in normal synaptic transmission; however, their dysregulation and overactivation are associated with excitotoxic neuronal damage as observed in AD. Therefore, targeting the NMDAR acts as therapeutic strategy to treat AD. This present study is focused on the identification of novel NMDA receptor antagonists, using molecular docking method. Ifenprodil is taken as the reference ligand, a well-known subunit-selective antagonist of the NMDA receptor that binds to GluN2B subunit. A structural similarity search was performed in the PubChem database, by taking Ifenprodil as a query ligand, that lead to the identification of 607 structural analogues, on further sorting, only 73 ligands were selected. The shortlisted ligands were then subjected to molecular docking analysis to evaluate ligand-protein interactions and the docking scores. The ligands exhibiting superior docking scores were further analysed. The ADME analysis was performed to assess the BBB permeability, GI absorption and other pharmacokinetic properties to ensure the CNS suitability. A total of eight compounds that exhibit the favourable docking scores along with acceptable pharmacokinetic properties were identified. These eight compounds may serve as potential candidates to treat AD, but are subjected to wet-lab experimentation.