Multiple molecular modelling studies on some derivatives and analogues of glutamic acid as matrix metalloproteinase-2...

Matrix metalloproteinase-2 (MMP-2) is a potential target in anticancer drug discovery due to its association with angiogenesis, metastasis and tumour progression. In this study, 67 glutamic acid derivatives, synthesized and evaluated as MMP-2 inhibitors, were taken into account for multi-QSAR modelling study (regression-based 2D-QSAR, classification-based LDA-QSAR, Bayesian classification QSAR, HQSAR, 3D-QSAR CoMFA and CoMSIA as well as Open3DQSAR). All these QSAR studies were statistically validated individually. Regarding the 3D-QSAR analysis, the Open3DQSAR results were better than CoMFA and CoMSIA, although all these 3D-QSAR models supported each other. The importance of biphenylsulphonyl moiety over phenylacetyl/naphthylacetyl moieties was established due to its association with favourable steric and hydrophobic characters. HQSAR, LDA-QSAR and Bayesian classification QSAR studies also suggested that the biphenylsulphonamido group was better than the phenylacetylcarboxamido function. Additionally, glutamines were proven to be far better inhibitors than isoglutamines. Observations obtained from the current study were revalidated and supported by the earlier reported molecular modelling studies. Depending on these observations, newer glutamic acid-based compounds may be designed further in future for potent MMP-2 inhibitory activity.