In silico study of MMP inhibition

Abstract

Lack of enzyme inhibition selectivity is frequently the major drawback preventing the development of enzyme inhibitors. Sulfonylhydrazides have recently been suggested to act as zinc ligands. Consequently, such derivatives potentially possess important industrial or therapeutic implications. DFT calculations (B3LYP/6–31G**+LANL2DZ theory level) of the binding modes and free energies of binding of a variety of N-acetyl-N′-sulfonylhydrazides in the presence of a Zn²⁺ ion embedded in an MMP active site model show that protonated and deprotonated sulfonylhydrazides bind the Zn²⁺ ion according to different modes. These results strongly suggest that sulfonylhydrazides can be developed as selective metalloprotease inhibitors, and the results of molecular docking computations fully support this hypothesis.