Role of hinge motion and ATP dynamics in factors for inversion stimulation FIS protein deduced while targeting drug resistant Orientia tsutsugamushi.

Orientia tsutsugamushi , the causative agent of scrub typhus has been found resistant to various classes of antibiotics such as penicillins, gentamycin and cephalosporins. Review of current literature suggests that the prevalence of scrub typhus has increased globally. Therefore, the current study has aimed at exploring the genome of O. tsutsugamushi to identify potential drug target proteins that can be used for developing novel antibiotics against the pathogen. Subtractive proteomics approach has revealed FIS as a potential drug target protein involved in two component system (TCS), a signaling pathway crucial for bacteria to survive and adjust in changing environmental conditions. Molecular docking studies have revealed compound-356 (CHEMBRIDGE-10040641-3710.356) as a potential inhibitor in both chains A and B of the FIS protein. Simulation results suggest that the docked complex has remained stable and compact throughout the 200 ns run. Significant conformational changes including the hinge motion was observed in the DNA binding domain. Furthermore, the presence of salt bridge between GLU910 and ARG417, rearrangement of interaction residues and displacement of ATP in the central AAA + domain upon binding to the inhibitor were also observed playing a role in stabilizing the protein structure. [Display omitted] • FIS protein revealed as potential drug target involved in TCSs pathway. • Compound-356 acts as potential inhibitor in both chains A and B of the FIS protein. • ATP plays significant role in holding the ligand within the central AAA + domain. • Hinge motion in the DBD is observed during simulation. • Inhibitor in the active pocket keeps protein stable without disrupting its hinge motion. [ABSTRACT FROM AUTHOR]