In Silico Drug Repurposing against Salmonella Typhimurium LT 2 Dam Protein

Abstract

The increasing prevalence of Multidrug-Resistant (MDR) pathogens has resulted in the failure of current antibiotics to effectively treat these infections. ComputerAided Drug Discovery CADD) has become a crucial tool in the drug discovery process recently. It has been demonstrated to be a successful method for screening lead compounds against target proteins within a short amount of time and with optimal resources. In the present study, a computational approach, CADD tools were employed to identify novel drug candidates against Salmonella enterica serovar Typhimurium LT2, targeting its essential gene, Dam. Virtual screening of various ligand libraries was conducted. From the initial library consisting of 21,000 compounds from natural products, 10,342 compounds from indole derivatives, 1,685 compounds from Kinase Inbibitors and 3,118 compounds from Nucleoside mimetics after ADME/Tox and druglikeness filters were narrowed down the number of compounds to 205 Natural Products, 462 Indole Derivatives, 6449 Kinase Inhibitors, and 654 Nucleoside Mimetics. The final screening from molecular docking and binding energy resulted in the identification of four lead compounds, Antineo plaston A10 and Cardamonin from natural products, 5-cyclopentaneamido-1-ethyl-N-(2 meth oxyethyl)-1H-indole-2-carboxamide from Indole Derivatives, 2[[anilino (oxo)methyl]amino]-4,5-dimeth oxybenzoic acid from Kinase Inhibitors and 3-[[[4-[2-(3,5-Dimethylpyrazol-1-yl)ethoxy]phenyl]methylamino]methyl]-1-(6methylpyrimidin-4-yl)pyrrolidin-3-ol from Nucleoside Mimetics were identified as potential leads. These compounds showed higher binding affinity with the target protein and lower binding efficiency for human hMAT1A protein compared to the reference compound S-Adenosyl methionine (SAM) and S-adenosyl homocysteine (SAH). The stability and strength of protein-ligand binding were observed through protein-ligand interactions, Density Functional Theory (DFT), analysis of frontier molecular orbitals and vibrational spectra. The results suggest that these compounds may be potential candidates for further exploration against other MDR pathogens prioritized by the World Health Organization (WHO).

Keywords: CADD, Multidrug-Resistant, Dam, essential gene, lead compounds