Synergistic application of target structure-based alignment and 3D-QSAR study of protein tyrosine phosphatase 1B (PTP1B) inhibitors

Protein tyrosine phosphatase 1B (PTP1B) has been demonstrated to play a key role in the negative signaling pathway of insulin. Potent and orally active PTP1B inhibitors are considered to be promising pharmacological agents for the treatment of type 2 diabetes and resistance to weight gain. CoMFA studies were performed on a set of PTP1B inhibitors, which are known to bind simultaneously to the active site as well as a sub-binding site. An alignment, based on eight different crystal structure complexes of PTP1B was carried out to study the synergistic application of the alignment on CoMFA. The CoMFA model with statistical parameters r_textcv ² = 0. 50 6,  r_textncv ² = 0. 9 8 5 r_{text{cv}}^{ 2} = 0. 50 6,;r_{text{ncv}}^{ 2} = 0. 9 8 5 , standard error of estimate 0.12, and F = 244.4 was found to be significant. The steric and electrostatic components presumably play an important role to achieve activity and selectivity in this series of molecules.