*3.2.1 Signaling peptide UA159sp (PDB id: 2I2J)*

The peptide-mediated quorum sensing in *S. mutans* is well conserved and regulates its genetic competence [28, 43, 44]. This signaling circuit plays regulatory roles in biofilm formation [43, 45, 46], stress response [47], and bacteriocin production, which are important virulence factors of this bacterium [43, 48].

#### **Figure 4.**

*Representations of the interactions between the three best ligands (compounds 2, 11, and 18) and the amino acid residues of Spap PDB id: 3OPU. Blue dashed lines represent hydrogen bonds and red dashed lines represent steric interactions.*

*Molecular Docking of Phytochemicals against* Streptococcus mutans *Virulence Targets… DOI: http://dx.doi.org/10.5772/intechopen.101506*

Quorum-sensing allows bacterial communication, providing benefits during host colonization, defense against competitors, and adaptation to the environment [43, 49]. The chemical details of the signaling molecules of this system in **S. mutans** are known and only UA159sp has been identified as a signal peptide in wild-type **S. mutans** strain [44].

In a study, conducted by Syvitski et al. [50], peptides in which three or more residues were deleted from the C-terminal region of the signaling peptide UA159sp did not induce genetic competence and inhibited, by competition, the quorum sensing activated by UA159sp. Disruption of the amphipathic α-helix by replacing Phe-7, Phe-11, or Phe-15 residues with a hydrophilic residue resulted in a significant reduction or complete loss of peptide activity. In contrast to peptides truncated at the C-terminal region, these peptides with amino acid substitutions did not compete with UA159sp to activate quorum sensing, suggesting that disruption of the hydrophobic face of the α-helix structure results in a peptide that is not capable of binding to the receptor. Therefore, residues of the C-terminal region of the signaling peptide in the quorum-sensing system of streptococci are extremely important.

Quorum-sensing inhibitor drug design enables the development of more specific treatments for biofilm-dependent infectious diseases [51]. A benefit of using quorum sensing inhibitor drugs is that they are less susceptible to antimicrobial resistance than other antimicrobials, as they exert a lower selective pressure and do not directly kill bacterial cells [52].

Docking with the signaling peptide UA159sp PDB id: 2I2J identified as the best ligands the compounds: erystagallin (11) (Edock = −84.98 kJ/mol), erycristagallin (10) (Edock = −83.99 kJ/mol), and methoxyficifolinol (1) (Edock = −79.76 kJ/ mol). In all ligands, the presence of hydrogen bonds with the Ser14 residue and steric interactions with the Ala18 residue is indicative of their importance for the stability of the interaction of these compounds with the active site (**Figure 5**).

#### *3.2.2 Signaling peptide TPC3 (PDB id: 2I2H)*

TPC3 peptide is a signal peptide synthesized by the mutant strain of **S. mutans** JH1005 that also can activate the quorum-sensing system.

For the signaling peptide TCP3 PDB id: 2I2H the best ligands were: erycristagallin (10) (Edock = −-99.74 kJ/mol), sophoraflavanone G (2) (Edock = −93.23 kJ/mol), and methoxyficifolinol (1) (Edock = −88.16 kJ/mol). As can be seen in **Figure 6**, hydrogen

#### **Figure 5.**

*Representations of the interactions between the three best ligands (compounds 11, 10, and 1) and the amino acid residues of the signal peptide UA159sp PDB id: 2I2J. Blue dashed lines represent hydrogen bonds and red dashed lines represent steric interactions.*

**Figure 6.**

*Representations of the interactions between the three best ligands (compounds 10, 2, and 1) and the amino acid residues of the signal peptide TCP3 PDB id: 2I2H. Blue dashed lines represent hydrogen bonds and red dashed lines represent steric interactions.*

bonds and steric interactions with Ala18 and Leu10 residues contributed to the energy reduction of these complexes, especially of the best ligands.
