In silico repurposing of a Novobiocin derivative for activity against latency associated Mycobacterium tuberculosis drug target nicotinate-nucleotide adenylyl transferase (Rv2421c)
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Date
2021
Journal Title
Journal ISSN
Volume Title
Publisher
Public Library of Science
Abstract
Nicotinamide-nucleotide adenylyl transferase (Rv2421c) was selected as a potential drug
target, because it has been shown, in vitro, to be essential for Mycobacterium tuberculosis
growth. It is conserved between mycobacterium species, is up-regulated during dormancy,
has a known 3D crystal structure and has no known human homologs. A model of Rv2421c
in complex with nicotinic acid adenine dinucleotide and magnesium ion was constructed
and subject tovirtual ligand screening against the Prestwick Chemical Library and the ZINC
database, which yielded 155 potential hit molecules. Of the 155 compounds identified five
were pursued further using an IC50 based 3D-QSAR study. The 3D-QSAR model validated
the inhibition properties of the five compounds based on R2 value of 0.895 and Q2 value of
0.944 compared to known inhibitors of Rv2421c. Higher binding affinities was observed for
the novel ZINC13544129 and two FDA approved compounds (Novobiocin sodium salt, Sulfasalazine).
Similarly, the total interaction energy was found to be the highest for Cromolyn
disodium system (-418.88 kJ/mol) followed by Novobiocin (-379.19 kJ/mol) and Sulfasalazine
with (-330.13 kJ/mol) compared to substrate DND having (-185.52 kJ/mol). Subsequent
in vitro testing of the five compounds identified Novobiocin sodium salt with activity against
Mycobacterium tuberculosis at 50 μM, 25μM and weakly at 10μM concentrations. Novobiocin
salt interacts with a MG ion and active site residues His20, Thr86, Gly107 and Leu164
similar to substrate DND of Mycobacterium tuberculosis Rv2421c. Additional in silico structural
analysis of known Novobiocin sodium salt derivatives against Rv2421c suggest Coumermycin
as a promising alternative for the treatment of Mycobacterium tuberculosis based
on large number of hydrogen bond interactions with Rv2421c similar in comparison to Novobiocin
salt and substrate DND.
Description
Keywords
Antitubercular agents, Drug repositioning, Mycobacterium tuberculosis, Novobiocin, Niacin
Citation
Cloete, R., Shahbaaz, M., Grobbelaar, M., Sampson, S. L., & Christoffels, A. (2021). In silico repurposing of a novobiocin derivative for activity against latency associated mycobacterium tuberculosis drug target nicotinate-nucleotide adenylyl transferase (Rv2421c). PLoS ONE, 16(November) doi:10.1371/journal.pone.0259348