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Theoretical study and molecular docking analysis of some inhibitors of dopamine transporter for the identification of potent antipsychotic therapeutic agents targeting schizophrenia mental disorder

Sabitu Babatunde Olasupo

Theoretical study and molecular docking analysis were performed on some Inhibitors of Dopamine Transporter as to develop a predictive and robust model as well as to elucidate binding mode and molecular interactions between the ligands (inhibitors) and the receptor targeting schizophrenia mental disorder as novel Antipsychotic agents. Density Functional Theory (DFT) approach was used to optimize the ligands at B3LYP/6-31G* at the ground state and Multi-linear regression of the genetic function approximation (MLR-GFA) method was employed in building Penta-parametric linear equation models. The best model with statistically significant parameters has squared correlation coefficient R2= 0.802, adjusted squared correlation coefficient R2adj = 0.767, Leave one out (LOO) cross validation coefficient (Q2) = 0.693, lack of fit score (LOF) = 0.406, R2Test = 0.77, ð??-randomization test (cR2p) = 0.714, Chi-squared (ê?³2) =0.026, bootstrapping (Systematic errors = 0.272) and Variance Inflation Factor (VIF) <2 . The obtained results were compared with standard validation parameters to prove the predictivity, reliability, and robustness of the model. Also, the mechanistic interpretation of the descriptors found in the model revealed that two out of five descriptors; MATS7s (32.3%) and RDF95m (30.4%) having a pronounced influence on the observed antipsychotic property of the compounds by their highest percentage contributions. Molecular docking analysis showed that the binding affinity of the selected ligands ranges from -10.05 to 9.0 kcal/mol with ligand 21 having the highest binding affinity (-10.05 kcal/mol). All the selected ligands displayed hydrogen bonds and hydrophobic interactions with the amino acid residues of the target (4M48) which could account for their higher binding energy. The developed model has passed the minimum threshold for an acceptable QSAR model and satisfied OECD principles of model development, it could, therefore, be employed as a blueprint for designing novel antipsychotic therapeutic agents with improved activity for the treatment of schizophrenia mental disorder.