Structural differences of matrix metalloproteinases with potential implications for inhibitor selectivity examined by the GRID/CPCA approach.

The matrix metalloproteinases (MMPs) are a family of proteolytic enzymes, which have been the focus of a lot of research in recent years because of their involvement in various disease conditions. In this study, structures of 10 enzymes (MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP12, MMP13, MMP14, and MMP20) were examined with the intention of highlighting regions that could be potential sites for obtaining selectivity. For this purpose, the GRID/CPCA approach as implemented in GOLPE was used. Counterions were included to take into account the different electrostatic properties of the proteins, and the GRID calculations were performed, allowing the protein side chains to move in response to interaction with the probes. In the search for selectivity, the MMPs are known to be a very difficult case because the enzymes of this family are very similar. The well-known differences in the S1' pocket were observed, but in addition, the pockets S3 and S2 called for attention. This is an observation that emphasizes the need for design of inhibitors exploiting the unprimed side of the active site, if possible, in combination with the S1' site. Despite small differences, a rational usage of the findings described in this work should make it possible to use a combination of the features of the individual enzyme pockets, making most of the MMP enzymes possible targets for selective inhibition. The results suggest the possibility of distinguishing between 8 of the 10 enzymes by this approach.