Prediction of MMP-9 inhibitory activity of N-hydroxy-α-phenylsulfonylacetamide derivatives by pharmacophore based modeling and 3-D QSAR studies

摘要

Matrix metalloproteinase-9 (MMP-9), also known as gelatinase B, is a MMP that is strongly associated with multiple cellular processes including proliferation, angiogenesis, and metastasis. Various studies have shown that N-hydroxy-α-phenylsulfonylacetamide (HPSAs) derivatives are promising and selective for the MMP-9 inhibition. In the present study, we have selected and reported 80 HPSAs derivatives as inhibitors of MMP-9 and performed structure-based 3-dimensional quantitative structure–activity relationship (3D-QSAR) studies to elucidate the important structural elements responsible for binding affinity. Developed pharmacophore models; QSAR model I contains 2 hydrogen-bond acceptors (A), 2 hydrogen-bond donors (D), and 1 aromatic ring (R) and QSAR model II contains 3 hydrogen-bond acceptors (A), 1 positive ionic (P), and 1 aromatic ring (R). The statistical results of QSAR models (I and II) such as good correlation coefficient (0.61 for I and 0.63 for II), good predictive power (0.84 and 0.77 for I and II, respectively) with low standard deviation (SD0.3 for both) strongly suggest that the developed models are virtuous for the future prediction of MMP-9 inhibitory activity of HPSAs derivatives. The geometry and features of pharmacophore were expected to be useful for further design and development of selective MMP-9 inhibitors.