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

Year 2020, , 179 - 196, 15.02.2020

Sabitu Babatunde Olasupo , Adamu Uzaıru Gideon Shallangwa , SANI Uba

https://doi.org/10.18596/jotcsa.577259

Cited By: 6

Abstract

The Norepinephrine transporter (NET) is a Na+/Cl- coupled
neurotransmitter transporter responsible for reuptake of released
norepinephrine (NE) into neural terminals in the brain, an important
therapeutic agent used in the treatment of psychiatric disorders. A
quantitative structural activity relationship (QSAR) investigation
was carried out on 50 Molecules of NET Inhibitors to investigate
their inhibitory potencies against norepinephrine transporter as
novel agents for anti-psychotic disorders. The molecules were
optimized by employing Density functional theory (DFT) with basis set
of B3LYP/6-31G*. The genetic function Algorithm (GFA) approach was
used to generate a highly predictive and statistically significant
model with good correlation coefficient R2 Train = 0.952, Cross
validated coefficient Q2cv = 0.870 and adjusted squared correlation
coefficient R2adj = 0.898. The predictability and accuracy of the
developed model was evaluated through external validation using test
set molecules, Y-randomization and applicability domain techniques.
The results of Molecular docking 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 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 this study are envisaged to provide very
important new insights into the molecular basis and structural
requirements that would help in designing more potent and more
specific therapeutic anti-psychotic agents.

Keywords

Norepinephrine transporter Inhibitors, antipsychotic, QSAR, Disorder, DFT

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