Recent Developments in the Design of Specific Matrix Metalloproteinase Inhibitors aided by Structural and Computational Studies

It has been 10 years since a 3-dimensional structure of the catalytic domain of a Matrix Metalloprotease (MMP) was revealed for the first time in 1994. More than 80 structures of different MMPs in apo and inhibited forms, determined by X-ray crystallography and NMR methods, have been published by the end of year 2003. A large number of very potent inhibitors have been disclosed in published and patent literature. Several MMP inhibitors entered clinical trials for the treatment of cancer and arthritis. Most of the first generation inhibitors have hydroxamic acid as the Zinc-binding group and have limited specificity. With the failure of these inhibitors in clinical trials, more efforts have been directed to the design of specific inhibitors with different Zn-binding groups in recent years. This review will summarize all the published structural information and focus on the inhibitors that were designed to take advantage of the nonprime side of the MMP active site using structural information and computational analysis. Representative structures from all MMPs are aligned to a target structure to provide a better understanding of the similarities and differences of the active site pockets. This analysis supports the view that the differences in the nonprime side pockets provide better opportunities for designing inhibitors with higher specificity. Published information on all the Zinc-binding groups of MMP inhibitors is reviewed for the first time. Pros and cons of inhibitors with non-hydroxamate Zinc-binding groups in terms of specificity, toxicity and pharmacokinetic properties are discussed.