Protocol for expediting drug targets search in S . Typhi through
subtractive genomics and the identification of lead-based novel small
Typhoid fever is transmitted by ingestion of polluted water,
contaminated food, and stool of typhoid-infected individuals, mostly in
developing countries with poor hygienic environments. To find novel
therapeutic targets and inhibitors, the complete genomes of eight
Salmonella Typhi strains were primarily subjected to the EDGAR
tool to predict the core genome (n=3207). Human non-homology (n=2450)
was followed by essential genes identification (n=37). The STRING
database predicted maximum protein-protein interactions, followed by
cellular localization. The virulent/immunogenic ability of predicted
genes were checked to differentiate drug and vaccine targets.
Furthermore, the 3D models of the identified putative proteins encoded
by the respective genes were constructed and subjected to druggability
analyses where only “highly druggable” proteins were selected for
molecular docking and simulation analyses. The putative targets include
ATP-dependent CLP protease proteolytic subunit, Imidazole glycerol
phosphate synthase hisH, 7,8-dihydropteroate synthase folP and
2,3-bisphosphoglycerate-independent phosphoglycerate mutase gpmI. A ZINC
drug-like library (n=12000) was screened against each identified targets
and top hits were selected based on H-bonds, RMSD and energy scores.
Finally, the ADMET properties for novel inhibitors ZINC19340748,
ZINC09319798, ZINC00494142, ZINC32918650 were optimized followed by
binding free energy (MM/PBSA) calculation for ligand-receptor complexes.
The findings of this work are expected to aid in expediting the
identification of novel protein targets and inhibitors in combating
typhoid Salmonellosis, in addition to the already existing therapies.