Pharmacophore Modeling Studies on Known MMP-9 Enzyme Inhibitors to Identify the Important Common Features

Abstract

Objective: In this study, pharmacophore models were generated to explain the structure-activity relationships by using the known MMP-9 inhibitors. Material and Method: Pharmacophore models were generated to explain the specification of the structure-activity relationships of common pharmacophoric sites of the known MMP-9 inhibitors. For this study Discovery Studio 3.5 software was used. A set of known MMP-9 inhibitors (NFH, Batimastat, Marimastat, Prinomastat, CGS-27023A, and Ro32-3555) were used for common feature pharmacophore generation method. Selected hypothesis included two hydrogen bond acceptor, one hydrogen bond donor, and one hydrophobic feature. Result and Discussion: All of the tested inhibitors except CGS-27023A and Ro32-3555 fitted the selected pharmacophore model perfectly. These two inhibitors did not fit the A2 feature. It can be concluded that A1, D1, and H1 features at the given positions could be necessary for the activity. Additionally, we compared the pharmacophore model with NFH and MMP-9 enzyme complex to identify the important interactions. At the given positions of all of the pharmacophoric features, there is an interaction with the protein. This is also supported our pharmacophore hypothesis. As a result, this pharmacophore model could be useful to design new small molecule inhibitors of MMP-9 enzyme.

Novel Matrix Metalloproteinase-9 (MMP-9) Inhibitors in Cancer Treatment

“…These two compounds cannot fit properly with the second HBA. Those results emphasize the importance of the presence of HBA, HBD, and HY pharmacophore points in the model to ensure the potential affinity and biological activity of MMP-9 inhibitors [84]. Moreover, a 3D pharmacophore model was developed from a set of sixty-four β-N-biaryl ether sulfonamide hydroxamate derivatives as potent MMP-9 inhibitors.…”