Exploiting the glycan receptor-binding site of PltB subunit in salmonella typhi toxin for novel inhibitors: An in-silico approach.

Salmonella typhi (S. typhi), a gram-negative bacterium responsible for gastroenteritis - typhoid - has continually evolved into drug-resistant strains with the most recent being the haplotype H58 strain. The haplotype H58 strain has spread across the globe causing outbreaks in countries such as Pakistan, Zimbabwe, and several underdeveloped regions located in parts of Asia, Central and Southern Africa. Treatment by conventional antibiotics is gradually failing as recorded in the affected countries, including Nigeria and Barcelona - Spain. Therefore, the research presented herein aims to identify novel compounds targeting the typhoid toxin of S. typhi which is responsible for several virulence factors associated with typhoid. In-silico methods that include virtual screening, molecular dynamics (MD) and computation of binding free energies were utilized. Our research identified furan derivatives as top-scoring lead compounds from a database of more than 1,5 million compounds curated from the ZINC20 database. Post docking analysis and trajectory analysis post-MD simulations showed that π - π interactions are vital to holding the ligand within the receptor pocket whereas hydrophobic and Van der Waals interactions are crucial for the overall bonding. Through docking, MD simulations and free energy computations, we hypothesize that ZINC000114543311, ZINC000794380763 and ZINC000158992484 (docking scores of -9.06, -8.20 and -8.12 in conjunction with ΔG values of -64.691, -63.670 and -59.024 kcal/mol, respectively) bear a great potential to pave the way to fighting antibiotic resistance for typhoid in both humans and animals. The compounds presented here can also be used as lead materials for designing other compounds targeting the Salmonella typhi toxin.