Curr Comput Aided Drug Des. 2017 Mar 1. doi: 10.2174/1573409913666170301120421. [Epub ahead of print]

Molecular Dynamics Simulations of Novel Potential Inhibitors for Penicillin Binding Protein 2B of the Resistant 5204 Strain of Streptococcus pneumoniae.

Suvaithenamudhan S, Parthasarathy S1.

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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.


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.


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 Analysis.


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.


These results suggest that the top five best hit compounds are found to be a promising gateway for the further development of anti pneumococcus therapeutics.

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PMID: 28260518 DOI: 10.2174/1573409913666170301120421