{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T19:01:41Z","timestamp":1785438101424,"version":"3.56.0"},"reference-count":78,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Portuguese Foundation for Science and Technology","award":["UID\/04423\/2025"],"award-info":[{"award-number":["UID\/04423\/2025"]}]},{"name":"Portuguese Foundation for Science and Technology","award":["UID\/PRR\/04423\/2025"],"award-info":[{"award-number":["UID\/PRR\/04423\/2025"]}]},{"name":"Portuguese Foundation for Science and Technology","award":["LA\/P\/0101\/2020"],"award-info":[{"award-number":["LA\/P\/0101\/2020"]}]},{"award":["UID\/04423\/2025"],"award-info":[{"award-number":["UID\/04423\/2025"]}],"id":[{"id":"https:\/\/ror.org\/00snfqn58","id-type":"ROR","asserted-by":"publisher"}]},{"award":["UID\/PRR\/04423\/2025"],"award-info":[{"award-number":["UID\/PRR\/04423\/2025"]}],"id":[{"id":"https:\/\/ror.org\/00snfqn58","id-type":"ROR","asserted-by":"publisher"}]},{"award":["LA\/P\/0101\/2020"],"award-info":[{"award-number":["LA\/P\/0101\/2020"]}],"id":[{"id":"https:\/\/ror.org\/00snfqn58","id-type":"ROR","asserted-by":"publisher"}]},{"name":"USFQ, Ecuador","award":["16897"],"award-info":[{"award-number":["16897"]}]},{"award":["16897"],"award-info":[{"award-number":["16897"]}],"id":[{"id":"https:\/\/ror.org\/01r2c3v86","id-type":"ROR","asserted-by":"publisher"}]},{"name":"SECIHTI\u2019s Project \u201cCiencia B\u00e1sica y de Frontera 2025\u201d","award":["CBF-2025-I-1213"],"award-info":[{"award-number":["CBF-2025-I-1213"]}]},{"award":["CBF-2025-I-1213"],"award-info":[{"award-number":["CBF-2025-I-1213"]}],"id":[{"id":"https:\/\/ror.org\/059ex5q34","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Bioactive peptides constitute a highly diverse and therapeutically relevant molecular class, yet their systematic exploration remains challenging because of the vast size, heterogeneity, and fragmented annotation of peptide chemical space. In this context, complex networks have emerged as a complementary computational framework for organizing, analyzing, and exploiting peptide diversity. This methodological review examines the main components of graph-based peptide informatics, from graph-based data integration and curated repositories to descriptor-based representations, similarity-driven network construction, and topology-informed analysis. We describe how peptide sequences can be projected into multidimensional reference spaces using molecular descriptors, aggregation operators, and unsupervised feature selection, and how these representations support the construction of Chemical Space Networks, Half-Space Proximal Networks, and Metadata Networks. Special attention is given to topological analysis, including threshold selection, community detection, and centrality-based identification of representative peptides and scaffolds. We also review the development of Multi-query Similarity Searching Models as training-independent, topology-guided alternatives to conventional supervised predictors. Finally, we highlight the implementation of these methodologies in computational resources such as StarPepDB, StarPep Toolbox, and StarPepWeb, which illustrate the transition of peptide network science from conceptual workflows to accessible, scalable, and reproducible infrastructures. Overall, complex networks are presented as a mature and interpretable paradigm for the structured exploration, analysis, and discovery of bioactive peptides.<\/jats:p>","DOI":"10.3390\/biom16071007","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T11:43:34Z","timestamp":1783683814000},"page":"1007","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Complex Networks in Bioactive Peptide Research: A Methodological Review"],"prefix":"10.3390","volume":"16","author":[{"given":"Kevin","family":"Castillo-Mendieta","sequence":"first","affiliation":[{"name":"International Max Planck Research School (IMPRS) for Molecular Biology, Georg-August Universit\u00e4t G\u00f6ttingen, Justus-von-Liebig-Weg 11, 37077 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9908-2418","authenticated-orcid":false,"given":"Guillermin","family":"Ag\u00fcero-Chapin","sequence":"additional","affiliation":[{"name":"Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), University of Porto, Terminal de Cruzeiros do Porto de Leix\u00f5es, Av. General Norton de Matos, 4450-208 Porto, Portugal"},{"name":"Department of Biology of Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7503-1528","authenticated-orcid":false,"given":"Edgar A. M\u00e1rquez","family":"Braz\u00f3n","sequence":"additional","affiliation":[{"name":"Grupo de Investigaciones en Qu\u00edmica y Biolog\u00eda, Facultad de Ciencias Exactas, Universidad del Norte, Carrera 51B, Km 5, v\u00eda Puerto Colombia, Barranquilla 081007, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6128-9504","authenticated-orcid":false,"given":"Jos\u00e9 R.","family":"Mora","sequence":"additional","affiliation":[{"name":"Grupo de Qu\u00edmica Computacional y Te\u00f3rica (QCT-USFQ), Departamento de Ingenier\u00eda Qu\u00edmica, Universidad San Francisco de Quito, Diego de Robles y V\u00eda Interoce\u00e1nica, Quito 170901, Pichincha, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3166-745X","authenticated-orcid":false,"given":"Noel","family":"P\u00e9rez-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Colegio de Ciencias e Ingenier\u00edas \u201cEl Polit\u00e9cnico\u201d, Universidad San Francisco de Quito (USFQ), Quito 170157, Pichincha, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8802-280X","authenticated-orcid":false,"given":"N\u00e9stor","family":"Cubill\u00e1n","sequence":"additional","affiliation":[{"name":"Programa de Qu\u00edmica, Facultad de Ciencias B\u00e1sicas, Universidad del Atl\u00e1ntico, Barranquilla 080003, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3962-7658","authenticated-orcid":false,"given":"C\u00e9sar R.","family":"Garc\u00eda-Jacas","sequence":"additional","affiliation":[{"name":"Investigador por M\u00e9xico, Secretar\u00eda de Ciencia, Humanidades, Tecnolog\u00eda e Innovaci\u00f3n (Secihti), Ciudad de M\u00e9xico 03940, Mexico"},{"name":"Unidad de Posgrado e Investigaci\u00f3n, Instituto Tecnol\u00f3gico de M\u00e9rida, Tecnol\u00f3gico Nacional de M\u00e9xico, Av. Tecnol\u00f3gico, Km. 4.5, M\u00e9rida 97000, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yovani","family":"Marrero-Ponce","sequence":"additional","affiliation":[{"name":"Facultad de Ingenier\u00eda, Universidad Panamericana, Augusto Rodin No. 498, Insurgentes Mixcoac, Benito Ju\u00e1rez, Ciudad de M\u00e9xico 03920, Mexico"},{"name":"Universidad San Francisco de Quito (USFQ), Grupo de Medicina Molecular y Traslacional (MeM&T), Colegio de Ciencias de la Salud (COCSA), Escuela de Medicina, Edificio de Especialidades M\u00e9dicas, and Instituto de Simulaci\u00f3n Computacional (ISC-USFQ), Diego de Robles y v\u00eda Interoce\u00e1nica, Quito 170157, Pichincha, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Akbarian, M., Khani, A., Eghbalpour, S., and Uversky, V.N. (2022). 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