Scaffold hopping for identification of novel D ₂ antagonist based on 3D pharmacophore modelling of illoperidone analogs

The dopamine D ₂ receptor is involved in the etiology of a number of disorders, such as Parkinson's disease, Huntington's Chorea, tardive dyskinesia and schizophrenia. Antagonism of D ₂ receptors is implicated in the treatment of various psychiatric disorders. In order to understand essential structural features required for D ₂ antagonism, this research article elaborates on the generation of a four-point 3D pharmacophore model which was extracted from a series of 45 novel 3-[[(aryloxy)alkyl]piperidinyl]-1,2-benzisoxazole derivatives. The best pharmacophore model generated consisted of four PRRR features: a positively charged group (P), and three aromatic rings (R). Based on the model generated, a statistically valid 3D-QSAR with good predictability (Q ₂ = 0.756) was derived. For the validation of the pharmacophore hypothesis, active compounds were docked against the 3D structure of the D ₂ receptor which was constructed through homology modeling. Further, the derived pharmacophorewas used as a query to search the Zinc 'clean drug-like' database. Hits retrieved were passed progressively through filters, such as fitness score, predicted activity and docking scores. The resulting hits present new scaffolds with a strong potential for D ₂ antagonist.