3D-QSAR, ADME-Tox In Silico Prediction and Molecular Docking Studies for Modeling the Analgesic Activity against Neuropathic Pain of Novel NR2B-Selective NMDA Receptor Antagonists

Abstract

A new class of selective antagonists of the N-Methyl-D-Aspartate (NMDA) receptor subunit 2B have been developed using molecular modeling techniques. The three-dimensional quantitative structure–activity relationship (3D-QSAR) study, based on comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models, indicate that steric, electrostatic and hydrogen bond acceptor fields have a key function in the analgesic activity against neuropathic pain. The predictive accuracy of the developed CoMFA model (Q2 = 0.540, R2 = 0.980, R2 pred = 0.613) and the best CoMSIA model (Q2 = 0.665, R2 = 0.916, R2 pred = 0.701) has been successfully examined through external and internal validation. Based on ADMET in silico properties, L1, L2 and L3 ligands are non-toxic inhibitors of 1A2, 2C19 and 2C9 cytochromes, predicted to passively cross the blood–brain barrier (BBB) and have the highest probability to penetrate the central nervous system (CNS). Molecular docking results indicate that the active ligands (L1, L2 and L3) interact specifically with Phe176, Glu235, Glu236, Gln110, Asp136 and Glu178 amino acids of the transport protein encoded as 3QEL. Therefore, they could be used as analgesic drugs for the treatment of neuropathic pain.