Background: Top five best hit compounds (ZINC59376795, ZINC60175365,
ZINC36922620, ZINC39550705 and ZINC36953975) were obtained through our high throughput virtual
screening (HTVS) analysis with resistant 5204-PBP2B (5204 Penicillin Binding Protein 2B) and
sensitive R6-PBP2B (R6 Penicillin Binding Protein 2B) proteins of Streptococcus pneumoniae. Objective:
To gain insight in molecular docking and dynamics simulations of these top five best hit compounds
with both resistant 5204-PBP2B and sensitive R6-PBP2B targets.
Methods: We have employed Glide XP docking and molecular dynamics simulations of these five
best hit compounds with 5204-PBP2B and R6-PBP2B targets. The stability analysis has been carried
out through DFT, prime-MM/GBSA binding free energy, RMSD, RMSF and Principal Component
Results: The reference drug, penicillin G forms stable complex with sensitive R6-PBP2B protein. Similar
stability is observed for the mutant resistant 5204-PBP2B with the top scoring compound
ZINC592376795 which implies that this compound may act as an effective potential inhibitor. The
compound ZINC59376795 forms a total of five hydrogen bonds with resistant 5204-PBP2B protein of
which three are with mutated residues. Similarly, the other four compounds including penicillin G also
form hydrogen bonds with mutated residue. The MD simulations and stability analysis of the complexes
of wild and mutant forms are evaluated for a trajectory period of 16ns and further MD simulations of
ZINC59376795 with resistant 5204-PBP2B and sensitive R6-PBP2B confirmed the stability for 50 ns.
Conclusion: These results suggest that the top five best hit compounds are found to be a promising
gateway for the further development of anti-pneumococcal therapeutics.