Multi criteria evaluation of schizophrenia drugs: DFT, ADMET, and molecular docking investigations

Schizophrenia is still a large psychiatric problem worldwide, therefore much study into the structural, electronics and pharmacokinetic properties of therapeutic drugs used in its treatment are needed. The present study has been performed by employing Density Functional Theory (DFT) calculations, molecular electrostatic potential (MEP) mapping, analytical Fukui function evaluation, ADMET profiling and molecular docking in an effort to comprehensively evaluate eight important antipsychotic drugs. DFT studies highlighted important electronic features. Global reactivity descriptors indicated a higher oxidative stability in aripiprazole, opposite to the marked reactivity sensitivity of haloperidol. FMO analysis and Fukui condensation maps suggested that nucleophilic localisation was mainly on the nitrogen lone-pairs, while electrophilic areas were on the phenyl ring motifs. Structural divergence was observed in Olanzapine and Haloperidol. Comprehensive ADMET and multi-endpoint toxicity profiling for understanding physiological disposition revealed that gastrointestinal absorption is a common limitation, but all tested drugs possess excellent blood-brain barrier (BBB) permeability needed for central nervous system target engagement, along with generation-dependent acute toxicity profiles. Toxicity screening showed that aripiprazole had the highest LD₅₀ (800 mg/kg) and minimum risks at the endpoints. Finally, target-directed molecular docking against human glycine transporter 1 (PDB ID: 8WFK) quantified binding architectures in the range of -7.3 to -10.0 kcal/mol. Risperidone showed the highest affinity (-10.0 kcal/mol) due to strong electrostatic interactions with the primary anchoring residue Asp474 and hydrophobic stabilisation through Tyr142, Trp322 and Pro383. The redocking validated the results with RMSD 1.24Å. The MEP maps confirmed that the binding affinity to GlyT1 is the large negative potential localisation around the hydrogen-bond accepting heteroatoms, as well as the large electrochemically neutral hydrophobic regions. These insights provide a crucial integrated framework for optimising the next generation antipsychotic drug design.