Computational approaches for the design of novel dopamine D 2 and serotonin 5-HT 2A receptor dual antagonist towards schizophrenia

Piperidine and piperazine derivatives exhibit a diverse range of biological applications, including antipsychotic activity. In this study, a dataset of molecules containing piperidine, piperazine moieties that possess serotonin 5-HT 2A and dopamine D 2 inhibitory activity have been chosen for Pharmacophore modeling, Quantitative Structure–Activity (3D-QSAR) Relationship, Molecular docking, and ADME studies. The pharmacophoric hypothesis was found to be AAHPRRR_1 having seven features as one H-bond acceptor (A), one hydrophobic (H), one positive ion acceptor (P), and three aromatic rings (R), with survival score = 6.465 and AUC = 0.92. Based on the best hypothesis, the ZINC-Data base was virtually screened to find out the lead molecules. 3D-QSAR model, including internal and external validation showed comparative molecular field analysis (CoMFA) against 5HT 2A ( q 2 = 0.552, R 2 = 0.889, and r 2 poured. = 0.653 and number of component 5) and comparative molecular similarity indices analysis (CoMSIA) ( q 2 = 0.599, R 2 = 0.893, and r 2 pred. = 0.617), for D 2 (CoMFA, q 2 = 0.577, R 2 = 0.863, and r 2 pred. = 0.598) (CoMSIA, q 2 = 0.532, R 2 = 0.82) all results exhibited better productivity and significant statistical reliability of the model. The docking study was carried out on the crystal structure of 5-HT 2A having PDB ID; 6A93 and D 2 receptor having PDB ID; 6CM4. The screened compound ZINC74289318 possess a higher docking score − 10.744 and − 11.388 than co-crystallized ligand docking score − 8.840 and − 10.06 against 5-HT 2A and D 2 receptor respectively. Further, ZINC74289318 was screened for all drug-likeness parameters and no showed violation of the Lipinski rule of five. Also, it was found to possess good bioavailability of 0.55 with synthetic accessibility of 4.42 which is greater than risperidone.