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So far, the scope of B cell and T cell epitope prediction has been directed exclusively towards peptidic antigens. Nevertheless, various non-peptidic molecular classes can be recognized by immune cells. These compounds have not been systematically studied yet, and prediction approaches are lacking. The ability to predict the epitope activity of non-peptidic compounds could have vast implications; for example, for immunogenic risk assessment of the vast number of drugs and other xenobiotics. Here we present the first general attempt to predict the epitope activity of non-peptidic compounds using the Immune Epitope Database (IEDB) as a source for positive samples. The molecules stored in the Chemical Entities of Biological Interest (ChEBI) database were chosen as background samples. The molecules were clustered into eight homogeneous molecular groups, and classifiers were built for each cluster with the aim of separating the epitopes from the background. Different molecular feature encoding schemes and machine learning models were compared against each other. For those models where a high performance could be achieved based on simple decision rules, the molecular features were then further investigated. Additionally, the findings were used to build a web server that allows for the immunogenic investigation of non-peptidic molecules (\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/tools-staging.iedb.org\/np_epitope_predictor\" xlink:type=\"simple\">http:\/\/tools-staging.iedb.org\/np_epitope_predictor<\/jats:ext-link>\n                    ). The prediction quality was tested with samples from independent evaluation datasets, and the implemented method received noteworthy Receiver Operating Characteristic-Area Under Curve (ROC-AUC) values, ranging from 0.69\u20130.96 depending on the molecule cluster.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1009151","type":"journal-article","created":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T13:43:09Z","timestamp":1645191789000},"page":"e1009151","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Towards the prediction of non-peptidic epitopes"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2982-388X","authenticated-orcid":true,"given":"Paul F.","family":"Zierep","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8957-7612","authenticated-orcid":true,"given":"Randi","family":"Vita","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6604-0019","authenticated-orcid":true,"given":"Nina","family":"Blazeska","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6034-2016","authenticated-orcid":true,"given":"Aur\u00e9lien F. A.","family":"Moumbock","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1381-0390","authenticated-orcid":true,"given":"Jason A.","family":"Greenbaum","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8457-6693","authenticated-orcid":true,"given":"Bjoern","family":"Peters","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3744-189X","authenticated-orcid":true,"given":"Stefan","family":"G\u00fcnther","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,2,18]]},"reference":[{"key":"pcbi.1009151.ref001","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1002\/jmr.768","article-title":"Immunoinformatics may lead to a reappraisal of the nature of B cell epitopes and of the feasibility of synthetic peptide vaccines.","volume":"19","author":"MHVV Regenmortel","year":"2006","journal-title":"J Mol Recognit"},{"key":"pcbi.1009151.ref002","first-page":"149","volume-title":"Advances in Virus Research.","author":"P Leinikki","year":"1993"},{"key":"pcbi.1009151.ref003","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1159\/000217682","article-title":"Epitope group specificity of six immunoassays for carcinoembryonic antigen","volume":"12","author":"OP B\u00f6rmer","year":"1991","journal-title":"Tumour Biol"},{"key":"pcbi.1009151.ref004","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/j.1470-8744.1988.tb00009.x","article-title":"Generation and epitope analysis of thyroid stimulating hormone-specific monoclonal antibodies for enzyme immunoassays","volume":"10","author":"SN Chow","year":"1988","journal-title":"Biotechnol Appl Biochem"},{"key":"pcbi.1009151.ref005","doi-asserted-by":"crossref","DOI":"10.1007\/978-94-011-3822-2","volume-title":"Immunoassays in Food and Agriculture","author":"A Paraf","year":"1991"},{"key":"pcbi.1009151.ref006","doi-asserted-by":"crossref","first-page":"D906","DOI":"10.1093\/nar\/gkl849","article-title":"SuperHapten: a comprehensive database for small immunogenic compounds","volume":"35","author":"S G\u00fcnther","year":"2007","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1009151.ref007","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1038\/nri1956","article-title":"The love\u2013hate relationship between bacterial polysaccharides and the host immune system","volume":"6","author":"SK Mazmanian","year":"2006","journal-title":"Nature Reviews Immunology"},{"key":"pcbi.1009151.ref008","article-title":"Immune Recognition of Fungal Polysaccharides.","volume":"3","author":"BD Snarr","year":"2017","journal-title":"J Fungi (Basel)."},{"key":"pcbi.1009151.ref009","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1111\/imr.12431","article-title":"The processing and presentation of lipids and glycolipids to the immune system","volume":"272","author":"VF Vartabedian","year":"2016","journal-title":"Immunol Rev"},{"key":"pcbi.1009151.ref010","doi-asserted-by":"crossref","first-page":"5580","DOI":"10.1016\/j.febslet.2006.08.029","article-title":"How T lymphocytes recognize lipid antigens","volume":"580","author":"G De Libero","year":"2006","journal-title":"FEBS Letters"},{"key":"pcbi.1009151.ref011","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s11882-009-0079-1","article-title":"Allergenicity of Carbohydrates and Their Role in Anaphylactic Events.","volume":"10","author":"SP Commins","year":"2010","journal-title":"Curr Allergy Asthma Rep"},{"key":"pcbi.1009151.ref012","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1159\/000066770","article-title":"Carbohydrate epitopes and their relevance for the diagnosis and treatment of allergic diseases","volume":"129","author":"R. van Ree","year":"2002","journal-title":"Int Arch Allergy Immunol"},{"key":"pcbi.1009151.ref013","first-page":"261","article-title":"Carrier function in anti-hapten immune responses. 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