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This study used virtual screening of DrugBank and ZINC15 to identify ritonavir as a selective IL-20RA ligand. 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Rational Identification of Ritonavir as IL-20 Receptor A Ligand Endowed with Antiproliferative Properties in Breast Cancer Cells. Int. J. Mol. Sci. 2025, 26, 1285. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms26031285  \nCopyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://creativecommons.org/](https://creativecommons.org/)[ ](https://creativecommons.org/)[licenses/by/4.0/](licenses/by/4.0/)) .  \n1 Dipartimento di Scienze della Salute, Università degli Studi “Magna Græcia” di Catanzaro, Campus Universitario “S. Venuta”, Viale Europa, 88100 Catanzaro, Italy; vmaggisano@unicz.it (V.M.);  \n[a.gargano@unicz.it](a.gargano@unicz.it) (A.G.); [maiuolo@unicz.it](maiuolo@unicz.it) (J.M.); [ortuso@unicz.it](ortuso@unicz.it) (F.O.); [bulotta@unicz.it](bulotta@unicz.it) (S.B.)  \n2 Associazione CRISEA—Centro di Ricerca e Servizi Avanzati per l’Innovazione Rurale, Località Condoleo, 88055 Belcastro, Italy  \n3 Net4Science Academic Spinoff, Università “Magna Græcia” di Catanzaro, Campus Universitario “S. Venuta”, Viale Europa, 88100 Catanzaro, Italy  \n4 Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, Università della Calabria, 87036 Rende, Italy; [francesca.deamicis@unical.it](francesca.deamicis@unical.it)  \n5 Centro Sanitario, Università della Calabria, 87036 Rende, Italy  \n* Correspondence: [alcaro@unicz.it](alcaro@unicz.it); Tel.: +39-0961-3694197 † These authors contributed equally to this work.  \nAbstract: Targeting the tumor microenvironment (TME) is an attractive strategy for developing new drugs with anticancer activity against triple-negative breast cancer (TNBC) . Interleukins (ILs) are key players in the TME cytokine network promoting cancer progression. Recent studies have highlighted the involvement of IL-20 receptor subunit alpha (IL-20RA) signalling in several cancers, including BC, in which IL-20RA is highly expressed, correlating with poor prognosis and influencing tumoral characteristics such as proliferation, cell death, invasiveness, and TME activity. Therefore, elucidating the role of the IL-20RA signalling pathway could form the basis for developing new therapeutic strategies. This study aimed to identify selective bioactive ligands able to affect IL-20RA activity. Virtual screening of over 310,000 compounds from both the DrugBank and ZINC15 databases identified four potential hit compounds tested for their anticancer activity against TNBC in vitro cell lines. Notably, Ritonavir, a well-known Human Immunodeficiency Virus Type 1 (HIV-1) protease inhibitor, significantly inhibited cell proliferation (about 40% at 50 µM, p \u003C 0.001) . IL-20 preincubation counteracted Ritonavir’s cytostatic effect while IL-20RA knockdown restored proliferation in Ritonavir-treated TNBC cells. In conclusion, these findings demonstrated that Ritonavir reduced TNBC cell proliferation through IL-20RA activity modulation, suggesting its potential repurposing as a therapeutic agent for TNBC management.  \nKeywords: virtual screening; DrugBank; ZINC15; TME; IL-20RA; ritonavir; TNBC  \n1. Introduction  \nCancer is a major societal, public health, and economic problem in the 21st century that caused 20 million new cases in the year 2022 alongside 9.7 million deaths [1] . Bre","cbCais2T25nYR0Tk","https://ap.wps.com/l/cbCais2T25nYR0Tk","pdf",3514298,18,"English","# Abstract\n# Keywords\n# Introduction","[{\"question\":\"What was the main goal of the study?\",\"answer\":\"To identify selective bioactive ligands capable of modulating IL-20RA activity for anticancer effects in TNBC.\"},{\"question\":\"How did the researchers identify candidate compounds?\",\"answer\":\"They performed virtual screening of over 310,000 compounds from DrugBank and ZINC15, then tested four hit compounds for anticancer activity in TNBC cell lines in vitro.\"},{\"question\":\"What role did ritonavir play in the IL-20RA pathway?\",\"answer\":\"Ritonavir significantly inhibited TNBC cell proliferation. IL-20 preincubation counteracted this cytostatic effect, and IL-20RA knockdown restored proliferation, indicating an IL-20RA-dependent mechanism.\"}]","Rational Identification of Ritonavir as IL-20 Receptor A Ligand Endowed with Antiproliferative Properties in Breast Cancer Cells | PDF",1790216279,45]