In silico design of potential drug lead compounds for dual inhibition of MurC and MurD ligases of Salmonella enterica serovar Typhi

Abstract

almonella enterica serovar Typhi is the causative agent of the systemic infection commonly known as typhoid fever. The rise of antibiotic resistance in Salmonella Typhi has brought about the need to develop novel drugs that can eliminate this bacterium by targeting previously unexploited steps in its cellular process. In this study, the MurC and MurD ligases of Salmonella Typhi were targeted for dual inhibition, where 6,699 compounds from the Traditional Chinese Medicine Systems Database were docked using Autodock Vina to these enzymes. The binders with the highest binding affinities from this database were used to design novel compounds in MarvinSketch, and the resulting high-binding affinity designed molecules were screened using the following criteria: molecular interaction with the receptor enzyme, Lipinski’s Rule of Five, solubility category, and number of rotatable bonds. Among all the compounds designed, the three molecules that has the potential to act as dual inhibitors are: Molecule 26 with a binding energy level of -10.2 kcal/mol for MurC and -9.0 kcal/mol for MurD, Molecule D with a binding energy level of -9.3 kcal/mol for MurC and -10.6 kcal/mol for MurD, and finally, molecule J with a binding energy level at -9.7 kcal/mol for MurC and -10.0 kcal/mol for MurD. Additional in vitro and in vivo tests can be done to further develop the potential of these compounds as antibacterial drugs.