The N-methyl-D-aspartate (NMDA) is the family of glutamate receptor, which is involved in controlling synaptic plasticity and memory function; but overactivation of this receptor results to excess intracellular calcium formation, triggers neuronal injury and also involves in several pathologies. Both ligand- and structure-based quantitative structure-activity relationship (QSAR), pharmacophore, docking and simulation studies have been performed on a set of structurally diverse inhibitors to explore prime molecular structural features involve for specific binding to NMDA, and vis-à-vis inhibiting enzyme activity. 3D QSAR studies, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models showed the importance of steric, electrostatic and hydrophobic features; while hydrogen bond acceptor and hydrophobic features are depicted as important pharmacophore features of the molecule. Molecular docking and simulation studies corroborated the consequence of the features obtained from ligand-based Bayesian model (AUROCcv = 0.878); 3D QSAR CoMFA (R2 = 0.895, se = 0.513, Q2 = 0.602, R2pred = 0.673); CoMSIA (R2 = 0.877, se = 0.555, Q2 = 0.615, R2pred = 0.727); hologram QSAR (Q2 = 0.812, R2 = 0.941, R2pred = 0.772), and pharmacophore models (Q2 = 0.926, R2 = 0.927, R2pred = 0.621). Presence of aromatic ring, hetero and halogen atoms along with alkyl group of molecular scaffold shows their importance for binding affinity to NMDA receptor. Stability of the complex is adjudged by both docking and simulation studies. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.