{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:01:33Z","timestamp":1787022093349,"version":"build-2736575974"},"reference-count":25,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2021,11,2]],"date-time":"2021-11-02T00:00:00Z","timestamp":1635811200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["UID 64751"],"award-info":[{"award-number":["UID 64751"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["UID 86539"],"award-info":[{"award-number":["UID 86539"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    Nicotinamide-nucleotide adenylyl transferase (Rv2421c) was selected as a potential drug target, because it has been shown,\n                    <jats:italic>in vitro<\/jats:italic>\n                    , to be essential for\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    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 R\n                    <jats:sup>2<\/jats:sup>\n                    value of 0.895 and Q\n                    <jats:sup>2<\/jats:sup>\n                    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\n                    <jats:italic>in vitro<\/jats:italic>\n                    testing of the five compounds identified Novobiocin sodium salt with activity against\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    at 50 \u03bcM, 25\u03bcM and weakly at 10\u03bcM concentrations. Novobiocin salt interacts with a MG ion and active site residues His20, Thr86, Gly107 and Leu164 similar to substrate DND of\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    Rv2421c. Additional\n                    <jats:italic>in silico<\/jats:italic>\n                    structural analysis of known Novobiocin sodium salt derivatives against Rv2421c suggest Coumermycin as a promising alternative for the treatment of\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    based on large number of hydrogen bond interactions with Rv2421c similar in comparison to Novobiocin salt and substrate DND.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0259348","type":"journal-article","created":{"date-parts":[[2021,11,2]],"date-time":"2021-11-02T15:09:28Z","timestamp":1635865768000},"page":"e0259348","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["In silico repurposing of a Novobiocin derivative for activity against latency associated Mycobacterium tuberculosis drug target nicotinate-nucleotide adenylyl transferase (Rv2421c)"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1966-0212","authenticated-orcid":true,"given":"Ruben","family":"Cloete","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohd","family":"Shahbaaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8138-5376","authenticated-orcid":true,"given":"Melanie","family":"Grobbelaar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha L.","family":"Sampson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Christoffels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,11,2]]},"reference":[{"issue":"7","key":"pone.0259348.ref001","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1001\/jama.282.7.677","article-title":"Global burden of tuberculosis","volume":"282","author":"C Dye","year":"1999","journal-title":"JAMA: the journal of the American Medical Association"},{"key":"pone.0259348.ref002","volume-title":"Global tuberculosis report 2018","author":"Organization WH","year":"2018"},{"issue":"5980","key":"pone.0259348.ref003","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1126\/science.1184784","article-title":"Tuberculosis: what we don\u2019t know can, and does, hurt us","volume":"328","author":"DG Russell","year":"2010","journal-title":"Science"},{"issue":"6685","key":"pone.0259348.ref004","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/31159","article-title":"Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence","volume":"393","author":"Cole St","year":"1998","journal-title":"Nature"},{"issue":"8","key":"pone.0259348.ref005","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/j.chembiol.2009.07.006","article-title":"Targeting NAD biosynthesis in bacterial pathogens: Structure-based development of inhibitors of nicotinate mononucleotide adenylyl transferase NadD","volume":"16","author":"L Sorci","year":"2009","journal-title":"Chemistry & biology"},{"issue":"14","key":"pone.0259348.ref006","doi-asserted-by":"crossref","first-page":"5229","DOI":"10.1021\/jm100377f","article-title":"Complexes of bacterial nicotinate mononucleotide adenylyltransferase with inhibitors: implication for structure-based drug design and improvement","volume":"53","author":"N Huang","year":"2010","journal-title":"Journal of medicinal chemistry"},{"issue":"1","key":"pone.0259348.ref007","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12859-016-0898-8","article-title":"Resistance related metabolic pathways for drug target identification in Mycobacterium tuberculosis","volume":"17","author":"R Cloete","year":"2016","journal-title":"BMC Bioinformatics"},{"issue":"12","key":"pone.0259348.ref008","doi-asserted-by":"crossref","first-page":"7693","DOI":"10.1074\/jbc.M114.628016","article-title":"Mycobacterial Nicotinate Mononucleotide Adenylyltransferase structure, mechanism, and implications for drug discovery","volume":"290","author":"IA Rodionova","year":"2015","journal-title":"Journal of Biological Chemistry"},{"key":"pone.0259348.ref009","doi-asserted-by":"crossref","first-page":"3381","DOI":"10.1093\/nar\/gkg520","article-title":"SWISS-MODEL: an automated protein homology-modeling server","volume":"31","author":"T Schwede","year":"2003","journal-title":"Nucleic acids research"},{"key":"pone.0259348.ref010","doi-asserted-by":"crossref","unstructured":"Bowers KJ, Chow DE, Xu H, Dror RO, Eastwood MP, Gregersen BA, et al. 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