{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T19:27:29Z","timestamp":1790278049304,"version":"4.1.0"},"reference-count":39,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005911","name":"Najran University","doi-asserted-by":"publisher","award":["Growth Funding Program grant code (NU\/GP\/SERC\/13\/264\u20133)."],"award-info":[{"award-number":["Growth Funding Program grant code (NU\/GP\/SERC\/13\/264\u20133)."]}],"id":[{"id":"10.13039\/501100005911","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pyruvate:ferredoxin oxidoreductase (PFOR) is a key Achilles\u2019 heel in anaerobic pathogens. We integrate electronic-structure calculations (DFT), cheminformatic QSAR metrics, and residue-resolved docking to distill a concise \u201crecognition code\u201d and translate it into practical design rules. Using nitazoxanide (Nita; \u0394G(bind) \u2248 \u221210.0 kcal\u00b7mol\u22121) as a well-established reference, productive binding requires a conserved triad: a hydrogen-bond donor addressing Thr-997 and Cys-840, a \u03c0\u2013\u03c0 stack with Phe-869, and a recurrent \u03c0\u2013\u03c3 contact to Thr-997 that orients the scaffold. Deacetylation to tizoxanide unmasks the phenolic donor and raises local electrophilicity, yet it also slightly loosens pocket packing (\u22129.6 kcal\u00b7mol\u22121). Strategic halogenation introduces a \u03c3-hole interaction near Pro-29, tightening pose geometry without disrupting the donor network; the lead analogue yields \u221210.1 kcal\u00b7mol\u22121, and two others match the reference by preserving the triad and hydrophobic belt. The result is a minimal, testable recipe\u2014retain the phenolic donor, enforce Thr-997\/Cys-840 and Phe-869, and add a calibrated halogen \u03c3-hole\u2014offering falsifiable predictions to surpass nitazoxanide and guiding synthesis and biophysical validation in targeted PFOR inhibition.<\/jats:p>","DOI":"10.3390\/ijms262311578","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T08:13:49Z","timestamp":1764576829000},"page":"11578","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["First-Principles Modeling of Nitazoxanide Analogues as Prospective PFOR-Targeted Antibacterials"],"prefix":"10.3390","volume":"26","author":[{"given":"Huda","family":"Alqahtani","sequence":"first","affiliation":[{"name":"Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3290-6635","authenticated-orcid":false,"given":"Islam","family":"Gomaa","sequence":"additional","affiliation":[{"name":"Nanotechnology Research Centre (NTRC), The British University in Egypt (BUE), Suez Desert Road, Cairo 11837, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2369-9315","authenticated-orcid":false,"given":"Ahmed","family":"Refaat","sequence":"additional","affiliation":[{"name":"Spectroscopy Department, National Research Centre, 33 El-Bohouth St., Dokki, Giza 12622, Egypt"},{"name":"Molecular Modeling and Spectroscopy Laboratory, Centre of Excellence for Advanced Science, National Research Centre, 33 El-Bohouth St., Dokki, Giza 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2224-2218","authenticated-orcid":false,"given":"M. S. A.","family":"Mansour","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0735-3162","authenticated-orcid":false,"given":"Raiedhah A.","family":"Alsaiari","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Science and Art, Najran University, Najran P.O. Box 1988, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4482-2992","authenticated-orcid":false,"given":"Moustafa A.","family":"Rizk","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Science and Art, Najran University, Najran P.O. Box 1988, Saudi Arabia"},{"name":"Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1186\/s11671-024-04085-7","article-title":"Synergistic Efficacy of ZnO Quantum Dots, Ag NPs, and Nitazoxanide Composite against Multidrug-Resistant Human Pathogens as New Trend of Revolutionizing Antimicrobial Treatment","volume":"19","author":"Gomaa","year":"2024","journal-title":"Discov. Nano"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"M\u00fcller, J., Boubaker, G., M\u00fcller, N., Uldry, A.C., Braga-Lagache, S., Heller, M., and Hemphill, A. (2024). Investigating Antiprotozoal Chemotherapies with Novel Proteomic Tools\u2014Chances and Limitations: A Critical Review. Int. J. Mol. 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