{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T13:04:01Z","timestamp":1789909441806,"version":"4.0.1"},"reference-count":37,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,5]],"date-time":"2026-04-05T00:00:00Z","timestamp":1775347200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005241","name":"Montreal Clinical Research Institute","doi-asserted-by":"publisher","award":["None"],"award-info":[{"award-number":["None"]}],"id":[{"id":"10.13039\/501100005241","id-type":"DOI","asserted-by":"publisher"}]},{"award":["None"],"award-info":[{"award-number":["None"]}],"id":[{"id":"https:\/\/ror.org\/05m8pzq90","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Understanding how viruses engage host cell surfaces is fundamental to infection biology and therapeutic development. While vaccines remain central to prevention, recent global crises have emphasized the need for complementary antiviral strategies that can be mobilized rapidly against both known and emerging pathogens. In this context, artificial intelligence (AI) systems for biomolecular structure prediction, culminating in AlphaFold 3, are reshaping what is experimentally and conceptually achievable. Here, we present \u201cInteractys-AI\u201d, a framework designed to exploit AI-based structural modeling to systematically map virus\u2013host protein\u2013protein interactions (PPIs) and connect them to actionable drug repurposing opportunities. Beyond a technical workflow, Interactys-AI reflects a broader transformation toward predictive and anticipatory antiviral discovery. We describe the conceptual foundations of the platform, its implementation, and its application to influenza A H5N1 hemagglutinin. We further discuss how structural AI may redefine preparedness strategies, highlight current limitations, and outline future directions toward real-time therapeutic hypothesis generation.<\/jats:p>","DOI":"10.3390\/biom16040541","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T04:10:27Z","timestamp":1775448627000},"page":"541","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Interactys-AI: Toward AI-Driven Structural Mapping of Virus\u2013Host Interfaces for Antiviral Repurposing and Pandemic Preparedness"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6444-7600","authenticated-orcid":false,"given":"Christian","family":"Poitras","sequence":"first","affiliation":[{"name":"Institut de Recherches Cliniques de Montr\u00e9al (IRCM), Montr\u00e9al, QC H2W 1R7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1306-0172","authenticated-orcid":false,"given":"Ali","family":"Harake","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al (CRCHUM), Montr\u00e9al, QC H2X 0A9, Canada"},{"name":"Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC H3C 3J7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0567-0284","authenticated-orcid":false,"given":"Nathalie","family":"Grandvaux","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al (CRCHUM), Montr\u00e9al, QC H2X 0A9, Canada"},{"name":"Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC H3C 3J7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1702-0692","authenticated-orcid":false,"given":"Benoit","family":"Coulombe","sequence":"additional","affiliation":[{"name":"Institut de Recherches Cliniques de Montr\u00e9al (IRCM), Montr\u00e9al, QC H2W 1R7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Evans, R., O\u2019Neill, M., Pritzel, A., Antropova, N., Senior, A., Green, T., \u017d\u00eddek, A., Bates, R., Blackwell, S., and Yim, J. (2021). Protein complex prediction with AlphaFold-Multimer. bioRxiv.","DOI":"10.1101\/2021.10.04.463034"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1038\/s41467-022-28865-w","article-title":"The accuracy of AlphaFold2 in predicting protein\u2013protein interactions","volume":"13","author":"Bryant","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Kim, A.R., Hu, Y., Comjean, A., Rodiger, J., Mohr, S.E., and Perrimon, N. (2024). Enhanced protein\u2013protein interaction discovery via AlphaFold-Multimer. bioRxiv.","DOI":"10.1101\/2024.02.19.580970"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"eabm4805","DOI":"10.1126\/science.abm4805","article-title":"Computed structures of core eukaryotic protein complexes","volume":"374","author":"Humphreys","year":"2021","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"D439","DOI":"10.1093\/nar\/gkab1061","article-title":"AlphaFold Protein Structure Database: Massively expanding the structural coverage of protein-sequence space with high-accuracy models","volume":"50","author":"Varadi","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.1038\/s41467-022-29394-2","article-title":"AF2Complex predicts direct physical interactions in multimeric proteins with deep learning","volume":"13","author":"Gao","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Poitras, C., and Coulombe, B. (2025). AI-powered identification of human cell surface protein interactors of the hemagglutinin glycoprotein of high-pandemic-risk H5N1 influenza virus. Viruses, 17.","DOI":"10.3390\/v17121638"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"eabe9403","DOI":"10.1126\/science.abe9403","article-title":"Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms","volume":"370","author":"Gordon","year":"2020","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/j.cell.2020.09.033","article-title":"SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2","volume":"183","author":"Clausen","year":"2020","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1126\/science.abd2985","article-title":"Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity","volume":"370","author":"Ojha","year":"2020","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1126\/science.abd3072","article-title":"Neuropilin-1 is a host factor for SARS-CoV-2 infection","volume":"370","author":"Daly","year":"2020","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1080\/17460441.2021.1909567","article-title":"Artificial intelligence in drug discovery: Recent advances and future perspectives","volume":"16","author":"Grisoni","year":"2021","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e2411325","DOI":"10.1002\/advs.202411325","article-title":"Applications of artificial intelligence in drug repurposing","volume":"12","author":"Wan","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Serrano, D.R., Luciano, F.C., Anaya, B.J., Ongoren, B., Kara, A., Molina, G., Ramirez, B.I., S\u00e1nchez-Guirales, S.A., Simon, J.A., and Tomietto, G. (2024). Artificial Intelligence (AI) Applications in Drug Discovery and Drug Delivery: Revolutionizing Personalized Medicine. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16101328"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1038\/s41573-023-00774-7","article-title":"Artificial intelligence for natural product drug discovery","volume":"22","author":"Mullowney","year":"2023","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrd.2018.168","article-title":"Drug repurposing: Progress, challenges and recommendations","volume":"18","author":"Pushpakom","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1038\/s41421-020-0153-3","article-title":"Network-based drug repurposing for novel coronavirus 2019-nCoV\/SARS-CoV-2","volume":"6","author":"Zhou","year":"2020","journal-title":"Cell Discov."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/nrd1468","article-title":"Drug repositioning: Identifying and developing new uses for existing drugs","volume":"3","author":"Ashburn","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_21","first-page":"573","article-title":"Artificial intelligence for drug discovery, biomarker development, and generation of novel chemistry","volume":"19","author":"Zhavoronkov","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1038\/s41587-019-0224-x","article-title":"Deep learning enables rapid identification of potent DDR1 kinase inhibitors","volume":"37","author":"Zhavoronkov","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.drudis.2020.10.010","article-title":"Artificial intelligence in drug discovery and development","volume":"26","author":"Paul","year":"2021","journal-title":"Drug Discov. Today"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1016\/j.neuron.2018.08.011","article-title":"Molecular Dynamics Simulation for All","volume":"99","author":"Hollingsworth","year":"2018","journal-title":"Neuron"},{"key":"ref_25","first-page":"37","article-title":"Molecular dynamics simulations: Advances and applications","volume":"8","author":"Hospital","year":"2015","journal-title":"Adv. Appl. Bioinform. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1146\/annurev-physchem-042018-052331","article-title":"Machine learning for molecular simulation","volume":"71","author":"Tkatchenko","year":"2020","journal-title":"Annu. Rev. Phys. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/s41467-024-55461-x","article-title":"Integrating artificial intelligence with mechanistic epidemiological modeling: A scoping review of opportunities and challenges","volume":"16","author":"Ye","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"107876","DOI":"10.1016\/j.compbiomed.2023.107876","article-title":"A machine learning-based universal outbreak risk prediction tool","volume":"169","author":"Zhang","year":"2024","journal-title":"Comput. Biol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1126\/science.aam8335","article-title":"Opportunities and challenges in modeling emerging infectious diseases","volume":"355","author":"Metcalf","year":"2017","journal-title":"Science"},{"key":"ref_30","first-page":"800","article-title":"Genome sequencing tracks outbreaks","volume":"371","author":"Kupferschmidt","year":"2021","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"726","DOI":"10.7326\/M20-1301","article-title":"Diagnostic testing for severe acute respiratory syndrome\u2013related coronavirus 2","volume":"172","author":"Cheng","year":"2020","journal-title":"Ann. Intern. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1038\/s41587-022-01475-z","article-title":"A proteome-scale map of the SARS-CoV-2\u2013human contactome","volume":"41","author":"Kim","year":"2023","journal-title":"Nat. Biotechnol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e03205-23","DOI":"10.1128\/mbio.03205-23","article-title":"A review of virus host factor discovery using CRISPR screening","volume":"15","author":"See","year":"2024","journal-title":"mBio"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1038\/s41588-022-01131-x","article-title":"Genome-wide CRISPR screens identify mucins as host factors modulating SARS-CoV-2 infection","volume":"54","author":"Biering","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/s41586-021-03493-4","article-title":"Multilevel proteomics reveals host perturbations by SARS-CoV-2","volume":"594","author":"Stukalov","year":"2021","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nrg2918","article-title":"Network medicine: A network-based approach to human disease","volume":"12","author":"Gulbahce","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1016\/j.cell.2011.02.016","article-title":"Interactome Networks and Human Disease","volume":"144","author":"Vidal","year":"2011","journal-title":"Cell"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/4\/541\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T04:31:59Z","timestamp":1775449919000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/4\/541"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,5]]},"references-count":37,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["biom16040541"],"URL":"https:\/\/doi.org\/10.3390\/biom16040541","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,5]]}}}