5-HT6 (serotonin, 5-hydroxytryptamine) antagonism has been proposed on a promising approach for treating cognitive impairment associated with neuropsychiatric disorders (e.g. Alzheimer’s disease, Schizophrenia). Using PHASE programme (Schrodinger-USA), pharmacophore generation and atom based 3D-QSAR analysis of earlier reported aryl sulphonamide and sulfone based 5-HT6 antagonists were studied to get insight into their structural requirements responsible for high affinity. The best pharmacophore model generated consisted of four features AAPR: two hydrogen bond acceptors (A), a positive ionisable group (P) and an aromatic ring (R). Based on model generated, a statistically valid 3D-QSAR with good predictability was developed. Developed QSAR model showed good coefficient of determination (R2 > 0.90), higher variance ratio (F > 20), significant values for Q2 = 0.67 and Pearson correlation coefficient (Pearson-R) = 0.83. Statistical results of the generated model are significant and excellent which strongly recommends that this model is acceptable for designing of various novel derivatives with different scaffolds and their biological activity prediction as novel, potent 5-HT6 antagonists in future.
