Identification and prioritization of promising lead molecules from Syzygium aromaticum against Sortase C from Streptococcus pyogenes : an in silico investigation.

Sortases are extracellular transpeptidases that play an essential role in the adhesion of secreted proteins to the peptidoglycan layer of the cell wall of Gram-negative bacteria. Sortases are an important drug target protein due to their involvement in synthesizing the peptidoglycan cell wall of Streptococcus pyogenes , and these are not found in Homo sapiens . In this study, initially, we have performed protein sequence analysis to understand the sequential properties of Sortase C. Next, a comparative protein modeling approach was used to predict the three-dimensional model of Sortase C based on the crystal structure of Sortase C from Streptococcus pneumoniae . Virtual screening with an in-house library of phytochemicals from Syzygium aromaticum and molecular docking studies were performed to identify the promising lead molecules. These compounds were also analyzed for their drug-like and pharmacokinetic properties. Subsequently, the protein-ligand complexes of the selected ligands were subjected to molecular dynamics (MD) simulations to investigate their dynamic behavior in physiological conditions. The global and essential dynamics analyses result implied that the Sortase C complexes of the proposed three lead candidates exhibited adequate stability during the MD simulations. Additionally, the three proposed molecules showed favorable MM/PBSA binding free energy values ranging from -13.8 +/- 9.41 to -56.6 +/- 8.82 kcal/mol. After an extensive computational investigation, we have identified three promising lead candidates (CID:13888122, CID:3694932 and CID:102445430) against Sortase C from S. pyogenes . The result obtained from these computational studies can be used to screen and develop the inhibitors against Sortase C from S. pyogenes . Communicated by Ramaswamy H. Sarma.