Pharmacophore Modeling, Atom Based 3D-QSAR and Docking Studies of Protein Tyrosine Phosphatase 1B Inhibitors

Inhibitors of Protein Tyrosine Phosphatase 1B (PTP 1B), a negative regulator of insulin signal transduction, have been explored as potential antidiabetic agents. In the present work a series of bromo-retrochalcones as PTP 1B inhibitors have been used for pharmacophore modeling, atom based 3D-QSAR and docking studies. A five-point pharmacophore with two hydrogen bond acceptors (A), two aromatic rings (R), and one hydrophobe (H) as pharmacophoric features was developed using PHASE. The pharmacophoric hypothesis was used to generate statistically significant 3D-QSAR models. The best model showed good PLS statistics characterized by survival score (9.306), cross-validated r(2) (Q(2)) (0.706), regression coefficient r(2) (0.861), Pearson-R (0.853), and F value (76.4). Taken together, the Partial least square (PLS) generated 3D-QSAR pharmacophore and regression cubes along with structure based drug design provided a three dimensional topological view of the active site that can be used for the rational modification of bidentate PTP 1B inhibitors.