In Silico Identification of Novel Inhibitors Targeting the Homodimeric Interface of Superoxide Dismutase from the Dental Pathogen .

The microaerophile , the main microaerophile responsible for the development of dental plaque, has a single cambialistic superoxide dismutase (SOD) for its protection against reactive oxygen species. In order to discover novel inhibitors of SOD, possibly interfering with the biofilm formation by this pathogen, a virtual screening study was realised using the available 3D-structure of SOD. Among the selected molecules, compound was capable of inhibiting SOD with an IC value of 159 µM. Its inhibition power was affected by the Fe/Mn ratio in the active site of SOD. Furthermore, also inhibited the activity of other SODs. Gel-filtration of SOD in the presence of showed that the compound provoked the dissociation of the SOD homodimer in two monomers, thus compromising the catalytic activity of the enzyme. A docking model, showing the binding mode of at the dimer interface of SOD, is presented. Cell viability of the fibroblast cell line BJ5-ta was not affected up to 100 µM . A preliminary lead optimization program allowed the identification of one derivative, , endowed with a 2.5-fold improved inhibition power. Interestingly, below this concentration, planktonic growth and biofilm formation of cultures were inhibited by , and even more by its derivative, thus opening the perspective of future drug design studies to fight against dental caries.