In silico repurposing of a Novobiocin derivative for activity against latency associated Mycobacterium tuberculosis drug target nicotinate-nucleotide adenylyl transferase (Rv2421c)

Ruben Cloete; Mohd Shahbaaz; Melanie Grobbelaar; Samantha L Sampson; Alan Christoffels

doi:10.1371/journal.pone.0259348

In silico repurposing of a Novobiocin derivative for activity against latency associated Mycobacterium tuberculosis drug target nicotinate-nucleotide adenylyl transferase (Rv2421c)

PLoS One. 2021 Nov 2;16(11):e0259348. doi: 10.1371/journal.pone.0259348. eCollection 2021.

Authors

Ruben Cloete¹, Mohd Shahbaaz¹, Melanie Grobbelaar², Samantha L Sampson², Alan Christoffels¹

Affiliations

¹ South African Medical Research Council Bioinformatics Unit, South African National Bioinformatics Institute, University of the Western Cape, Bellville, South Africa.
² Faculty of Medicine and Health Sciences, Division of Molecular Biology and Human Genetics, DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Stellenbosch University, Stellenbosch, Cape Town, South Africa.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antitubercular Agents
Drug Repositioning
Mycobacterium tuberculosis*
Niacin
Novobiocin
Nucleotidyltransferases

Substances

Antitubercular Agents
Novobiocin
Niacin
Nucleotidyltransferases
glutamine-synthetase adenylyltransferase

Grants and funding

Research reported in this publication was supported by the South African Medical Research Council and the National Research Foundation (NRF). SLS is funded by the South African Research Chairs Initiative of the Department of Science and Innovation and NRF of South Africa, award number UID 86539. AC is funded by the South African Research Chairs Initiative of the Department of Science and Innovation and NRF of South Africa, award number UID 64751. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.