In silico Studies on Potential Inhibitors of the Penicillin Binding Protein 2B (PBP2B) of the Resistant G54 and Intermediate-resistant Hungary 19A-6 and SP195 Strains of Streptococcus Pneumoniae

Abstract

Background: Mutations in Penicillin Binding Protein 2B (PBP2B) lead to resistance against commercial β-lactam antibiotics among some strains of Streptococcus pneumoniae. In this study, the molecular mechanism of resistance and the alternate strategy for controlling the Penicillin Binding Protein 2B (PBP2B) of resistant G54 and the two intermediate-resistant Hungary19A-6 and SP195 strains of Streptococcus pneumoniae are determined using an in silico approach. Methods: In this study, we considered four ligand compounds, namely ZINC59376795, ZINC36922620, ZINC39550705, and ZINC36953975 of the ZINC database, identified through high-throughput screening (HTS) study for the resistant strain (5204-PBP2B). Glide XP docking and molecular dynamic simulation studies were performed on the PBP2B of the three resistant strains chosen for this study. The stability analysis was performed with prime-MM/GBSA, and the binding free energy, RMSD, and RMSF were also evaluated. Results: Out of the four ligands, the ZINC39550705 ligand was found to form a stable complex with PBP2B of all three strains. Furthermore, this ZINC39550705 ligand was observed to form four hydrogen bonds with the PBP2B of all three strains. Molecular dynamics simulations were performed with these four selected ligands and targets. The resulting binding pattern, RMSD, RMSF, and hydrogen bond calculation analyses provide deeper insight into the molecular interactions of these four selected ligands with the PBP2B of the three resistance strains of S. pneumoniae. Conclusion: The interaction of the selected ligand molecules and PBP2B of the resistant strains of S. pneumoniae revealed that hydroxyl amino acid Thr at position 224, acidic amino acids including Glu at positions 301, 245, and 240, amidic amino acids, Asn at positions 265 and 260, and aliphatic amino acid Gly at the 302 position had a crucial role in the formation of hydrogen bonds with most of the selected ligands that contributed to the stability of the complexes. The molecular dynamics simulation further confirmed that the stability of ligand ZINC39550705–PBP2B of all mutant strains was higher compared to other ligand-protein complexes evaluated in the present study. Selected ligand molecules showed significant properties of the inhibitor to be used against the resistant strains of S. pneumoniae, and the ligand ZINC39550705, in particular, is a potential alternative to commercial β-lactam antibiotics.