Computer-aided drug design and in silico pharmacokinetics predictions of some potential antipsychotic agents

Abstract The target of many drugs for the treatment of psychiatric disorders as well as neurological conditions are majorly relied on monoaminergic systems. In continuation of our previous study, computer-aided drug design approach was employed to design new inhibitors of norepinephrine transporter as potential antipsychotic agents. The significant contribution of some descriptors (AlogP, AATS7i and ATSC3p) in the developed QSAR model and the result of molecular docking simulations from our previous study informed the selection of compound 2 as the lead compound for the design of new inhibitors. Subsequently, ten (10) hypothetical inhibitors were designed with improved pharmacological properties as potential antipsychotic agents when compared the results with a known drug (Atomoxetine). The molecular docking analysis of the designed inhibitors revealed good biochemical interactions toward the active site of the biological target (receptor) with the binding affinities ranges from -7.2 to -7.6 kcal/mol, while the binding affinity of the lead compound and the referenced drug (Atomoxetine) were found to be 7.1 kcal/mol and 6.5 kcal/mol respectively. An appreciable number of hydrogen bonds were formed between amino acid residues of the protein target and all the designed inhibitors when compared to that of the lead compound. Likewise, the computed numerical values of all the descriptors in the designed inhibitors were significantly improved. These remarkable quality observed in the designed inhibitors could be ascribed to the structural modification by electrophilic substitutions (NH2, -OH, -OCH3, -CH3, NO2, -CF3, -F and Cl) at different positions of the lead compound owing to the influence of heteroatoms in the substituents as revealed by descriptors in the QSAR model. Similarly, drug-likeness and bioavailability evaluation showed that all the designed inhibitors obeyed Lipinski's rule of five. The ADMET properties revealed that all the designed inhibitors possessed excellent pharmacological properties. Similarly, toxicity risk assessments of some selected inhibitors showed that most of the selected inhibitors are non-AMES mutagenicity and none of the selected inhibitors is carcinogens. Against this background, the hypothetical designed inhibitors could be subjected to further experimental investigations prior to their development and optimization as novel antipsychotic drugs.