{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T05:01:40Z","timestamp":1789794100724,"version":"4.0.1"},"reference-count":41,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:00:00Z","timestamp":1789171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012190","name":"Ministry of Science and Higher Education","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012190","id-type":"DOI","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/05dwvd537","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Despite advances in oncology, cancer remains a leading cause of mortality worldwide, and both \u03bc-opioid receptor (MOR) and dopamine D2 receptor (D2R) signaling have been implicated in the regulation of tumor proliferation, survival, and progression, positioning them as attractive targets for multifunctional anticancer strategies. In the present study, a series of novel casomorphin\u2013ranatensin hybrid peptides were designed, synthesized, and evaluated as putative dual-target anticancer agents combining MOR and D2R pharmacophores. Among the evaluated analogues, KAZO_5.2 and KAZO_7.2 reduced viability of HCT116 colorectal cancer cells in a dose- and time-dependent manner, with a modest selectivity ratio compared to non-tumorigenic MCF 10A cells. Both compounds showed favorable docking scores toward MOR and D2R, while single 100 ns molecular dynamics trajectories showed that the peptides remained associated with their respective receptor models over the simulated timescale. Partial reversal of the viability-reducing effect by naloxone suggested involvement of opioid-sensitive pathways, while only low baseline MOR expression was detected in HCT116 cells under our experimental conditions, consistent with a possible contribution of additional receptor-mediated mechanisms to the observed activity. Neither compound induced pronounced apoptosis or cell cycle arrest, suggesting cytostatic rather than cytotoxic effects. Both peptides exhibited negligible hemolytic activity and high proteolytic stability in human plasma, with intact peptides remaining predominant after 24 h of incubation at 37 \u00b0C. These findings identify casomorphin\u2013ranatensin hybrids as a promising scaffold for dual-target anticancer peptide development, warranting further structural optimization and mechanistic investigation.<\/jats:p>","DOI":"10.3390\/molecules31183221","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T09:34:01Z","timestamp":1789378441000},"page":"3221","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rational Design of Putative Dual-Target Opioid-Dopaminergic Casomorphin\u2013Ranatensin Hybrid Peptides: Computational Modeling and Preliminary Antiproliferative Evaluation"],"prefix":"10.3390","volume":"31","author":[{"given":"Krystian","family":"Ma\u0142ek","sequence":"first","affiliation":[{"name":"Department of Biomedical Research, National Medicines Institute, 00-725 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"G\u00f3rski","sequence":"additional","affiliation":[{"name":"Department of Inorganic Chemistry, Faculty of Pharmacy, Medical University of Gdansk, 80-416 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5302-3797","authenticated-orcid":false,"given":"\u0141ukasz","family":"Szeleszczuk","sequence":"additional","affiliation":[{"name":"Department of Organic and Physical Chemistry, Medical University of Warsaw, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna K.","family":"Laskowska","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Microbiology, Medical University of Warsaw, 02-091 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuzanna","family":"Markowska","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biology, Medical University of Warsaw, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1876-1321","authenticated-orcid":false,"given":"Sebastian","family":"Granica","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biology, Medical University of Warsaw, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4006-2682","authenticated-orcid":false,"given":"Anna","family":"Pogorzelska","sequence":"additional","affiliation":[{"name":"Department of Biomedical Research, National Medicines Institute, 00-725 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Koch","sequence":"additional","affiliation":[{"name":"Maria Sklodowska-Curie Medical Academy in Warsaw, 03-411 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Pielaszkiewicz","sequence":"additional","affiliation":[{"name":"Maria Sklodowska-Curie Medical Academy in Warsaw, 03-411 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jagoda","family":"Michniewicz","sequence":"additional","affiliation":[{"name":"Maria Sklodowska-Curie Medical Academy in Warsaw, 03-411 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5335-3043","authenticated-orcid":false,"given":"Wojciech","family":"Kamysz","sequence":"additional","affiliation":[{"name":"Department of Inorganic Chemistry, Faculty of Pharmacy, Medical University of Gdansk, 80-416 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1209-9477","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"Milczarek","sequence":"additional","affiliation":[{"name":"Department of Biomedical Research, National Medicines Institute, 00-725 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0275-3017","authenticated-orcid":false,"given":"Karol","family":"Sikora","sequence":"additional","affiliation":[{"name":"Department of Inorganic Chemistry, Faculty of Pharmacy, Medical University of Gdansk, 80-416 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8389-0920","authenticated-orcid":false,"given":"Patrycja","family":"Kleczkowska","sequence":"additional","affiliation":[{"name":"Maria Sklodowska-Curie Medical Academy in Warsaw, 03-411 Warsaw, Poland"},{"name":"Department of Nursing and Other Health Professions, Center of Postgraduate Medical Education, 01-826 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,12]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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