Discovery of a Novel Thiourea Derivative Targeting Alpha‐2‐Macroglobulin as a Potential Antimicrobial Agent Against XDR Salmonella typhi: An Integrated In Silico and In Vitro Study

The emergence of extensively drug‐resistant Salmonella typhi as a major menace to global health rationalizes the pressing demand for discovering novel drug contenders that may target unconventional proteins and provide new avenues for antimicrobials development. In the present study, we retrieved the previously submitted sequence of a fairly unique protein, alpha‐2‐macroglobulin (a protease inhibitor involved in protecting S. typhi from host proteases) from the NCBI database. Subsequently, structure‐based virtual screening of compounds from the PubChem database was performed. Five novel compounds were short‐listed based on binding scores. After analyzing ADME and drug‐likeness potential, thiourea and benzamide were selected for MD simulations and in vitro antimicrobial study through the broth micro dilution method. A novel thiourea derivative, C‐4, was identified, exhibiting a binding affinity of −7.03 kcal/mol with the alpha‐2‐macroglobulin binding pocket and ensuring complete growth inhibition at 5 mM concentration, along with favorable pharmacokinetics and a suitable drug‐likeness profile.