{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T07:53:31Z","timestamp":1791014011893,"version":"4.1.0"},"reference-count":87,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T00:00:00Z","timestamp":1790985600000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100010798","name":"Sunway University","doi-asserted-by":"publisher","award":["GRTIN\u2010RAG(02)\u2010DDSAI\u201002\u20102025"],"award-info":[{"award-number":["GRTIN\u2010RAG(02)\u2010DDSAI\u201002\u20102025"]}],"id":[{"id":"10.13039\/501100010798","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chem Biol Drug Des"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Latent tuberculosis (TB), caused by dormant, non\u2010replicating\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    <\/jats:styled-content>\n                    (\n                    <jats:italic>Mtb<\/jats:italic>\n                    ), afflicts an estimated 1.7 billion individuals globally and remains a principal barrier to TB eradication. Dormant bacilli are phenotypically tolerant to conventional antibiotics and survive through continued dependence on oxidative phosphorylation (OXPHOS) and the electron transport chain (ETC), making bioenergetic enzymes, including the F1Fo\u2010ATP synthase, cytochrome\n                    <jats:italic>bcc:aa<\/jats:italic>\n                    3 supercomplex, Type II NADH dehydrogenase (NDH\u20102) and cytochrome\n                    <jats:italic>bd<\/jats:italic>\n                    oxidase, compelling drug targets. This review proposes and rigorously analyses a synergistic, multi\u2010scale computational workflow as a uniquely powerful paradigm for discovering anti\u2010persister agents. The workflow cascades across four integrated stages: (1) dormancy\u2010specific Quantitative Structure\u2013Activity Relationship (QSAR) modelling using hypoxic assay data, with predictive models achieving\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    values of 0.83\u20130.98; (2) rational scaffold design and pharmacophore\u2010guided hit expansion against structurally validated bioenergetic targets, incorporating bioisosteric replacement and fragment merging strategies; (3) structure\u2010based molecular docking exploiting high\u2010resolution cryo\u2010EM structures (resolution \u2264\u20092.67\u2009\u00c5), with clinically validated inhibitors such as Bedaquiline (BDQ) yielding docking scores of \u221212.3 to \u221215.8\u2009kcal\/mol; and (4) advanced Molecular Dynamics (MD) simulation under physiologically relevant conditions, including Constant pH MD (CpHMD) at phagosomal pH\u20094.5 and all\u2010atom mycomembrane models. A critically underexplored dimension, multi\u2010target drug discovery, is systematically examined, focusing on the design of dual\u2010pharmacophore inhibitors that simultaneously engage NDH\u20102 and cytochrome\n                    <jats:italic>bd<\/jats:italic>\n                    oxidase, thereby raising the genetic barrier to resistance. By framing discovery as a logical progression from statistical correlation (QSAR) through structural hypotheses (scaffold design and docking) to dynamic atomistic validation (MD), this review provides a rigorous, quantitatively grounded computational roadmap for the next generation of anti\u2010persister therapeutics.\n                  <\/jats:p>","DOI":"10.1111\/cbdd.70408","type":"journal-article","created":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T07:25:21Z","timestamp":1791012321000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Multi\u2010Scale Computational Framework for Anti\u2010Persister Tuberculosis Drug Discovery"],"prefix":"10.1111","volume":"108","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4840-0460","authenticated-orcid":false,"given":"Said","family":"Moshawih","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy, Department of Pharmaceutical Sciences Al\u2010Ahliyya Amman University  Amman Jordan"},{"name":"Faculty of Data Science and Information Technology INTI International University  Nilai Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anguraj","family":"Moulishankar","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Integrated Drug Discovery Centre Acharya &amp; BM Reddy College of Pharmacy  Bengaluru Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9084-4818","authenticated-orcid":false,"given":"Chee Yan","family":"Choo","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Universiti Teknologi MARA  Shah Alam Selangor Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6686-7019","authenticated-orcid":false,"given":"Khang Wen","family":"Goh","sequence":"additional","affiliation":[{"name":"Faculty of Data Science and Information Technology INTI International University  Nilai Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3713-7900","authenticated-orcid":false,"given":"Chrismawan","family":"Ardianto","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Universitas Airlangga  Surabaya Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azam Che","family":"Idris","sequence":"additional","affiliation":[{"name":"Faculty of Engineering and Technology, School of Computing and Artificial Intelligence Sunway University  Sunway City Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6971-1383","authenticated-orcid":false,"given":"Long Chiau","family":"Ming","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Universitas Airlangga  Surabaya Indonesia"},{"name":"Faculty of Medical and Life Sciences, School of Pharmacy Sunway University  Sunway City Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,3]]},"reference":[{"issue":"2","key":"e_1_2_8_2_1","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1007\/s11030-021-10254-y","article-title":"2D\u2010QSAR Modeling and Two\u2010Fold Classification of 1, 2, 4\u2010Triazole Derivatives for Antitubercular Potency Against the Dormant Stage of \n                     Mycobacterium tuberculosis","volume":"26","author":"Aher R. B.","year":"2022","journal-title":"Molecular Diversity"},{"issue":"4","key":"e_1_2_8_3_1","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1080\/1062936X.2022.2066175","article-title":"Molecular Docking\u2010Based Interactions in QSAR Studies on \n                     Mycobacterium tuberculosis\n                   ATP Synthase Inhibitors","volume":"33","author":"Ahmed S.","year":"2022","journal-title":"SAR and QSAR in Environmental Research"},{"issue":"1","key":"e_1_2_8_4_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.xpro.2022.101971","article-title":"Liquid Chromatography\u2010Mass Spectrometry\u2010Based Protocol to Measure Drug Accumulation in Mycobacterium Tuberculosis and Its Host Cell","volume":"4","author":"Ahn Y.\u2010M.","year":"2023","journal-title":"STAR Protocols"},{"key":"e_1_2_8_5_1","article-title":"Hypochlorous Acid Has Emerged as a Potential Alternative to Conventional Antibiotics due to Its Broad\u2010Spectrum Antimicrobial Activity","volume":"2766","author":"Akl M. M.","year":"2023","journal-title":"International Journal of Clinical Microbiology and Biochemical Technology"},{"issue":"27","key":"e_1_2_8_6_1","doi-asserted-by":"crossref","first-page":"24903","DOI":"10.1039\/D6RA01548D","article-title":"Discovery of Caralluma\u2010Derived Pregnane Glycosides as Potent and Selective Cholinesterase Inhibitors: Integrated In Silico and In\u00a0Vitro Evaluation","volume":"16","author":"Al\u2010Karmalawy A. 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