Uncovering Hidden Antibacterial Potential: A Computational Discovery of FDA‐Approved Drugs against ThiL Enzyme

Abstract Antimicrobial resistance (AMR) is a global health concern, necessitating the development of novel strategies that are effective against drug‐resistant organisms. One promising strategy to counteract AMR is to target untapped molecular targets with existing drugs. Thiamine monophosphate kinase (ThiL) is an unexplored target for antibacterial therapy, as it is an essential enzyme for thiamine biosynthesis in pathogens but is absent in humans, making it a promising, selective antibacterial target. Here, we repurposed 2000 FDA‐approved drugs against the ThiL enzyme via computational approaches to evaluate the binding affinity and stability of the compounds within the binding pocket. Among the tested compounds, naldemidine and vidarabine displayed favorable glide scores, suggesting strong interactions with the key residues present in the binding pocket. Furthermore, a 100 ns molecular dynamics simulation was performed to determine the stability of the complex. The findings depicted the sustained binding interactions of the compounds with the ThiL active residues, indicative of a potential inhibitory effect on enzyme activity. This study emphasized the viability of ThiL as a novel unexplored target and demonstrated the advantages of a drug repurposing strategy in facilitating the identification of promising antibacterial agents. This dual approach pioneer new therapeutic avenues while addressing the AMR.