Combining network pharmacology and computational approaches for screening of apiaceae-derived phytochemicals as inhibitors of DNA polymerase III in streptococcus pyogenes causing streptococcal toxic shock syndrome

Streptococcus pyogenes (S. pyogenes), a pathogen responsible for various severe infections, including streptococcal toxic shock syndrome (STSS), poses a significant therapeutic challenge worldwide. This study aims to explore the structural and functional properties of the DNA polymerase III subunit beta of S. pyogenes, identify potential phytochemical inhibitors, and evaluate their drug-like properties using computational methods. The DNA polymerase III subunit beta of S. pyogenes was successfully characterized, and its interactions with 60 phytochemicals from the Apiaceae family were predicted. ADMET analysis indicated that several compounds possessed desirable properties, including good solubility and high drug-likeness. Alpha-carotene emerged as a lead candidate exhibiting promising binding affinity and favorable interactions in docking studies. Additionally, to enhance the potency of the target compound, fragment optimization was performed, resulting in the development of a novel lead compound. Toxicity analysis indicated a low risk for adverse effects. Moreover, molecular dynamics simulations revealed that Alpha-carotene and DNA polymerase-III maintained stability with RMSD values below 4.3 Å. RMSF analysis showed significant flexibility in specific regions, reflecting effective interactions and increased stability over time. Overall, this study provides a comprehensive assessment of the DNA polymerase III subunit beta of S. pyogenes and its interactions with potential phytochemical inhibitors. Alpha-carotene, in particular, demonstrates significant potential as a therapeutic agent against S. pyogenes infections. These findings require further experimental validation for the potential development of novel antimicrobial agents against S. pyogenes.