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

The microaerophile Streptococcus mutans , the main microaerophile responsible for the development of dental plaque, has a single cambialistic superoxide dismutase ( Sm SOD) for its protection against reactive oxygen species. In order to discover novel inhibitors of Sm SOD, possibly interfering with the biofilm formation by this pathogen, a virtual screening study was realised using the available 3D-structure of Sm SOD. Among the selected molecules, compound ALS-31 was capable of inhibiting Sm SOD with an IC 50 value of 159 µM. Its inhibition power was affected by the Fe/Mn ratio in the active site of Sm SOD. Furthermore, ALS-31 also inhibited the activity of other SODs. Gel-filtration of Sm SOD in the presence of ALS-31 showed that the compound provoked the dissociation of the Sm SOD homodimer in two monomers, thus compromising the catalytic activity of the enzyme. A docking model, showing the binding mode of ALS-31 at the dimer interface of Sm SOD, is presented. Cell viability of the fibroblast cell line BJ5-ta was not affected up to 100 µM ALS-31 . A preliminary lead optimization program allowed the identification of one derivative, ALS-31-9 , endowed with a 2.5-fold improved inhibition power. Interestingly, below this concentration, planktonic growth and biofilm formation of S. mutans cultures were inhibited by ALS-31 , and even more by its derivative, thus opening the perspective of future drug design studies to fight against dental caries.