Abstract
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 B3LYP/6-31G*. The genetic function Algorithm (GFA) approach was used to generate a highly 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. 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.
Highlights
Psychotic disorder is a clinical syndrome of mental disorders in which some loss of contact with reality has occurred and it is generally applied to persons whose mental functioning is sufficiently impaired to interfere with their capacity to meet the ordinary demand of life [1]
quantitative structural activity relationship (QSAR) study was explored to investigate the structure–activity relationship of 50 compounds with distinguishing organic fragments acting as norepinephrine transporter (NET) inhibitors
A data set of 50 compounds was divided into a training set of 36 compounds used in developing the model and a test set of 14 compounds was used to evaluate the predictive ability of the QSAR model for the inhibition of norepinephrine transporter
Summary
Psychotic disorder is a clinical syndrome of mental disorders in which some loss of contact with reality has occurred and it is generally applied to persons whose mental functioning is sufficiently impaired to interfere with their capacity to meet the ordinary demand of life [1]. Psychotic disorders are common to all countries and cause immense human suffering, social exclusion, disability, poor quality of life, staggering economic and social costs. It is estimated that one in every four people have a mental disorder [1]. The combined costs of mental disorder, including loss of productivity, loss of earning due to illness and social costs, are estimated to total at least USD 113 billion annually [2]. The major depressive disorders (MDDs) had been estimated as the second largest global burden among all diseases by 2030 which makes the discovery of novel and efficacious anti-psychotic drugs very urgent [3]. Persons with psychotic disorder are at risk for complications and derivatives effects of psychosis such as suicide attempts, substance abuse, homelessness, victimization by others and committing act of violence [4]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
