Targeting protein tyrosine phosphatase to unravel possible inhibitors for Streptococcus pneumoniae using molecular docking, molecular dynamics simulations coupled with free energy calculations

Protein tyrosine phosphatase (PTP-CPS4B) is a signaling enzyme that is essential for a wide range of cellular processes, like metabolism, proliferation, survival and motility. Studies suggest that PTPs are vital for the production of Wzy-dependent capsule in bacteria, making it a valuable target for the discovery of pneumonia associated anti-virulence antibacterial agents. Present study aims at identifying the potential drug candidates to be exploited in inhibiting the growth of Streptococcus pneumonia targeting PTP-CPS4B. The present study exploits the molecular docking potential coupled with molecular dynamic simulation as well as free energy calculations to identify potential inhibitors of PTP-CPS4B. Libraries of known and unknown compounds were docked into the active site of PTP-CPS4B using MOE. The compounds with best binding affinity and orientation were subjected to MD simulations and free energy calculations. Top three compounds based on their binding energy and well composed interaction pattern obtained from molecular docking study were subjected to MD simulations and were compared to reported antibiotic drugs. MD Simulation studies have shown that the presence of an inhibitor inside the active site reduces protein flexibility as evident from RMSD, RMSF and Principal component analyses. MD simulations identified a transition from extended to bended motional shift in loop α6 of the PTP-CPS4B in ligand bound state. This flexibility was reported in the RMSF analysis and verified by the visual investigation of the loop α6 at different time intervals during the simulation. Free energy of binding affinity (computed using MMPBSA &MMGBSA approach) and the interaction patterns obtained from MD trajectory indicate that compound ZN1 (−31.50 Kcal/mol), ZN2 (−33.14 Kcal/mol) and ZN3 (−26.60 Kcal/mol) are potential drug candidates against PTP-CPS4B. Residue wise decomposition study helped in identifying the role of individual amino acid towards the overall inhibition behavior of the compounds. PCA analysis has led to the conclusion that the behavior of PTP-CPS4B inhibitors causes conformational dynamics that can be used to describe the protein inhibition mechanism. The outcome reveals that this study provide enough evidences for the consideration of ZN1, ZN2, ZN3 as potential PTP-CPS4B inhibitors and further in vitro and in vivo studies may prove their therapeutic potential. [Display omitted]