Characterization of Druggable Genome for the Identification of Potential Therapeutic Candidates in Human Pathogen: Vibrio Cholerae

Abstract

Vibrio cholerae is the etiologic agent of the diarrheal disease cholera. Vibrios are Gram negative rod shape bacteria. This water-borne pathogen is attained through drinking of tainted water or eating contaminated food. The horizontal gene transfer of the virulence genes and the pathogenicity islands is the prominent cause of the emergence of new strains of V. cholerae and this instigates the research towards the identification of novel drugs. The objective of current study is to characterize and identify the common potential therapeutic drug targets against V. cholerae strains namely O395, LMA3984-4 and IEC224 by applying hierarchal in silico subtractive genomic approach accompanied by molecular docking and molecular dynamic (MD) simulation studies. After successful screening of druggable candidates, on the basis of set parameters, a potential drug target candidate vibE was selected. VibE is crucial for the synthesis of vibrobactin which belongs to biosynthesis of siderophore pathway. Siderophores have applications in medicine for antibiotics for improved drug targeting. Therefore, it is one of the most viable candidates for drug development. To this aim molecular modeling was carried out to gain insights into active site and modeling was performed via MODELLER and web servers. Best modeled structure was selected and used for molecular docking studies. Total 106 compounds library were prepared for docking and compound 103 was the best docked compound with a GOLDScore of 75.7. Moreover, time dependent dynamic behaviour of docked complexes were analyzed using MD simulation studies. MD trajectories analysis revealed the flexibility of loop region to stabilize the binding of ligand and target protein and hydrogen bonding pattern was also rearranged. These conformational changes suggested the potential of compound 103 to act as lead compound.