In Silico Identification of Novel Inhibitors Targeting the Homodimeric Interface of Superoxide Dismutase from the Dental Pathogen <i>Streptococcus mutans</i>

Abstract

The microaerophile Streptococcus mutans, the main microaerophile responsible for the development of dental plaque, has a single cambialistic superoxide dismutase (SmSOD) for its protection against reactive oxygen species. In order to discover novel inhibitors of SmSOD, possibly interfering with the biofilm formation by this pathogen, a virtual screening study was realised using the available 3D-structure of SmSOD. Among the selected molecules, compound ALS-31 was capable of inhibiting SmSOD with an IC50 value of 159 µM. Its inhibition power was affected by the Fe/Mn ratio in the active site of SmSOD. Furthermore, ALS-31 also inhibited the activity of other SODs. Gel-filtration of SmSOD in the presence of ALS-31 showed that the compound provoked the dissociation of the SmSOD 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 SmSOD, 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.

Keywords

• Superoxide dismutase
• <i>Streptococcus mutans</i>
• virtual screening
• novel inhibitors
• antibiofilm activity
• dental plaque