Abstract

Multidrug resistance trait acquired by Salmonella Typhi, the causative agent of typhoid fever in different parts of the world has exacerbated the treatment outcome of the disease creating more public health concern. DHFR is an essential enzyme involved in the folate metabolic pathway and plays an essential role in the biosynthesis of RNA, DNA and protein in living cells and there are no DHFR inhibitors in clinical use against infections caused by Salmonella Typhi currently. This study aimed to identify potential drug candidates against S. Typhi from existing DHFR inhibitors using computational techniques. DrugBank and PubChem databases were searched for DHFR inhibitors to create a library needed for molecular docking. Amino acid sequence of Salmonella Typhi DHFR was retrieved from NCBI database was modeled using SWISS-MODEL. Discovery Studio was then used for protein preparation and visualization, and PyRx was used for molecular docking. All the compounds were found to exhibit favorable binding score against S. Typhi DHFR. Top hit compounds identified were Talotrexin, Aminopterin, Methotrexate and Fanotaprim with binding energies of -10.7, -10.2, -10.0 and -10.0 Kcal/mol respectively. All the top hit compounds have many hydrogen bonds and hydrophobic interactions which can account for the favorable binding scores observed. The favorable binding scores translates into higher binding affinity, thus suggesting them as priority compounds for antibacterial validation. This finding suggest that the four top hits are promising drug candidates that can be experimentally validated for the discovery of new drugs against typhoid fever.