In silico Integrative Approach to Identify Druggable Candidates in Klebsiella pneumoniae: A Multi-drug Resistant Pathogen

Abstract

Untimely discontinuation and misuse of therapeutic agents paired with emergence of new strains has imparted resistivity to pathogens. This demands development of more directed antibacterial agents. Klebsiella pneumoniae, a Gram negative, rod shaped bacterium is a life threatening multi-drug resistant (MDR) pathogen primarily involved in pneumonia. Multi-drug resistant behaviors of this emerging pathogen, initiate the research towards the identification of novel drugs. Statting point of this study was to identify and characterize the potential druggable targets in multiple strains of K. pneumaniae via a hierarchical in silica genome subtraction. Druggable targets were characterized qualitatively through a number of filters leading to the identification of a promising drug target candidate, citrate lyase subunit beta (citE). Unavailability of experimentally determined structure of citE, directed utilization of homology modeling technique to predict the structure. Best modeled structure was selected and used for molecular docking studies. Molecular docking protocol classified compound 47, as the ligatld best able to fit the binding pocket. Molecular dy namics (MD) simulations are playing a promising role in the development of therapeutic drugs. Thus, molecular dynamics was steered to simulate citE; a seventy nanosecond MD simulation illustrated a steady binding pattern ofligand in the protein's active site. Pursuing this, trajectory analysis was implemented to assess various characteristics of the docked system in terms of function of time. Dynamical flexibility of C-terminal domain was ob served. It is established hom the current work that more relaxed and improved structure of citE was produced which can be scrutinized for further analysis. Key findings of the study can be employed to guide the design of targeted citE inhibitory drugs.