Abstract:
The 21st century's foremost public health concern is the widespread occurrence of antibiotic
resistance. The chronic carriage of Salmonella typhi. is the primary source of enteric fever
transmission and perforation of resistant typhoid especially among children in developing
countries. However, the paradigm to ‘disarm’ the bacteria instead of killing it directly can augment
our dwindling antimicrobial arsenal with limited resistance. In this context, the Shikimate pathway
exclusive to bacteria is a desirable target for the generation of antibacterial therapies. The enzyme
3-dehydroquinate dehydratase type 1 (DHQ1) in Salmonella typhi. is a validated and crucial
therapeutic target because of its key role in the bacterial aromatic amino acid production pathway.
The goal of the current investigation is to ascertain which bioactive substances have inhibitory
action against the DHQ1 enzyme. The protein data bank (PDB) provided the protein's three dimensional structure. To identify potential anti-typhoidal compounds, structure-based virtual
screening (SBVS) was performed using 551 natural and anti- infection compounds from ApexBio
database. About 206 compounds out of 551 were filtered based on physicochemical properties and
Lipinki’s rule and went through the molecular docking process. The top ten ligands (Cabotegravir,
Imatinib, Prulifloxacin, Limonin, Silibinin, Atovaquone, Betamethasone Valerate GSK1324726A,
Isavuconazole, and Raltegravir) were chosen based on their greatest binding affinities, which
ranged from -9.8 to -9.1 (kcal/mol). Moreover, PASS analysis was used to prioritise the best
inhibitory chemical by performing
ADMET analysis, bioactivity prediction, and pharmacokinetic property prediction. Additionally,
RMSF values (root mean square fluctuation) from molecular dynamic modelling demonstrated
that the docked protein-ligand combination was stable. Experiments conducted in vitro and in vivo
will also help to clarify the safe and effective therapeutic role of the substances that are prioritized.
