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

dc.contributor.authorCloete, Ruben
dc.contributor.authorShahbaaz, Mohd
dc.contributor.authorChristoffels, Alan
dc.date.accessioned2022-08-12T10:45:48Z
dc.date.available2022-08-12T10:45:48Z
dc.date.issued2021
dc.description.abstractNicotinamide-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.en_US
dc.identifier.citationCloete, 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.0259348en_US
dc.identifier.urihttps://doi.org/10.1371/journal.pone.0259348
dc.identifier.urihttp://hdl.handle.net/10566/7725
dc.language.isoenen_US
dc.publisherPublic Library of Scienceen_US
dc.subjectAntitubercular agentsen_US
dc.subjectDrug repositioningen_US
dc.subjectMycobacterium tuberculosisen_US
dc.subjectNovobiocinen_US
dc.subjectNiacinen_US
dc.titleIn silico repurposing of a Novobiocin derivative for activity against latency associated Mycobacterium tuberculosis drug target nicotinate-nucleotide adenylyl transferase (Rv2421c)en_US
dc.typeArticleen_US

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