Conceptual Structure-Based Drug Design and Discovering of Novel Inhibitors of Norepinephrine Transporter (NET) as Potential Antipsychotic Agents for Mental Disorder

The inhibition of norepinephrine transporter (NET) plays an important role in the treatment of a psychiatric disorder. The present work employed a fast, simple, accurate and cost-effective cheminformatics approach using computer-aided structured-based drug design (SBDD) technique to complement our previous study. From our previous work, compound 2 was selected as the template compound for the design because of its better biological activity, lied within the applicability domain of the developed model and above all, it possessed good pharmacological attributes. As a consequence, Ten (10) hypothetical compounds were designed with better pharmacological properties as potential antipsychotic agents when compared the results with a standard drug (Atomoxetine). All the designed compounds displayed optimal molecular interactions with significant binding affinities (ranges from − 7.2 to − 7.6 kcal/mol) toward the active site of the biological target.  Besides, all the designed compounds possessed a higher number of hydrogen bonds which could be linked to the structural modification and incorporation of electrophilic substituents (NH2, –OH, –OCH3, –CH3, NO2, –CF3, –F and –Cl) at different positions in the pharmacophore of the template compound compared to the standard drug with a lower binding affinity of − 6.1 kcal/mol. An outstanding molecular interaction was observed in the designed compound 2i among the selected compounds which could be attributed to the presence of two strongly activating substituents (–OH and −OCH3) at the ortho and meta positions in the pharmacophore (–Chlorophenyl) of the compound. Similarly, drug-likeness and bioavailability assessments revealed that none of the designed compounds including the standard drug violates the criteria stipulated by Lipinski’s rule of five. Likewise, the ADMET/Pharmacokinetics investigations showed that all the designed compounds possessed outstanding pharmacological properties, good oral bioavailability, excellent human gastrointestinal absorption a remarkable blood–brain barrier (BBB) permeability evidenced from the BOILED Egg graphics. More so, toxicity evaluation of the selected compounds showed that all the selected compounds are non-AMES mutagenicity and non-carcinogenicity. Interestingly, none of the selected compounds portend to be a human ether-a-go-go-related gene (hERG) cardiovascular toxicity. Hence, it is envisaged that the present study would serve as a promising prototype for further in vivo and experimental investigations in the discovery and development of more potent antipsychotic drugs.