QSAR analysis and molecular docking simulation of norepinephrine transporter (NET) inhibitors as anti-psychotic therapeutic agents

The norepinephrine transporter (NET) is a Na(+)/Cl(−) coupled neurotransmitter transporter responsible for reuptake of released norepinephrine (NE) into nerve terminals in the brain, a key therapeutic used in the treatment of psychiatric disorders. A quantitative structural activity relationship (QSAR) study was performed on 50 compounds of NET inhibitors to investigate their inhibitory potencies against norepinephrine transporter as novel drugs for anti-psychotic disorders. The compounds were optimized by employing Density functional theory (DFT) with basis set of B(3)LYP/6-31G*. The genetic function Algorithm (GFA) approach was used to generate a highly predictive and statistically significant model with good correlation coefficient R(2)(Train) = 0.952 Cross validated coefficient Q(2)(cv) = 0.870 and adjusted squared correlation coefficient R(2)(adj) = 0.898. The predictability and accuracy of the developed model was evaluated through external validation using test set compound, Y-randomization and applicability domain techniques. The results of Molecular docking analysis by using two neurotransmitter transporters PDB ID 2A65 (resolution = 1.65 Å) and PDB ID 4M48 (resolution = 2.955 Å) showed that two of the ligands (compound 12 and 44) having higher binding affinity were observed to inhibit the targets by forming hydrogen bonds and hydrophobic interactions with amino acids of the two receptors respectively. The results of these studies would provide important new insight into the molecular basis and structural requirements to design more potent and more specific therapeutic anti-psychotic drugs/agents.