Quantitative Structure-Activity Relationship (QSAR) Studies and Molecular docking Simulation of Norepinephrine Transporter (NET) Inhibitors as Anti-psychotic Therapeutic Agents

Abstract

The Norepinephrine transporter (NET) is a Na+/Cl- coupled neurotransmitter transporterresponsible for reuptake of released norepinephrine (NE) into neural terminals in the brain, animportant therapeutic agent used in the treatment of psychiatric disorders. A quantitative structuralactivity relationship (QSAR) investigation was carried out on 50 Molecules of NET Inhibitors toinvestigate their inhibitory potencies against norepinephrine transporter as novel agents for antipsychotic disorders. The molecules were optimized by employing Density functional theory (DFT) withbasis set of B3LYP/6-31G*. The genetic function Algorithm (GFA) approach was used to generate ahighly predictive and statistically significant model with good correlation coefficient R2Train = 0.952,Cross validated coefficient Q2cv = 0.870 and adjusted squared correlation coefficient R2adj = 0.898. Thepredictability and accuracy of the developed model was evaluated through external validation usingtest set molecules, Y-randomization and applicability domain techniques. The results of Moleculardocking simulation 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 numbers 12 and44) having higher binding affinity were observed to inhibit the targets by forming hydrogen bonds andhydrophobic interactions with amino acids of the two receptors respectively. The results of this studyare envisaged to provide very important new insights into the molecular basis and structuralrequirements that would help in designing more potent and more specific therapeutic anti-psychoticagents.