In Silico Drug Repurposing Against Salmonella typhimurium LT2 Dam Protein
Date
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Department of Biotechnology
Abstract
The increasing prevalence of Multidrug-Resistant (MDR) pathogens has resulted in
the failure of current antibiotics to effectively treat these infections. Computer Aided
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, Antineoplaston
A10 and Cardamonin from natural products, 5-cyclopentaneamido-1-ethyl-N-(2methoxyethyl)-1H-indole-2-carboxamide
from Indole Derivatives, 2 [[anilino(oxo)methyl]amino]-4,5-dimethoxybenzoic
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