{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T23:29:39Z","timestamp":1783121379724,"version":"3.54.6"},"reference-count":78,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T00:00:00Z","timestamp":1622764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union 2014\u20132020 PON Ricerca e Innovazione grant from the Italian Ministry of Education, University and Re-search, entitled \u201cPROGEMA\u2014Processi Green per l\u2019Estrazione di Principi Attivi e la Depurazione di Matrici di Scarto e Non\u201d","award":["ARS01_00432"],"award-info":[{"award-number":["ARS01_00432"]}]},{"name":"PJ_RIC_FFABR_2017_ Grant \u2013 University of Palermo","award":["005832"],"award-info":[{"award-number":["005832"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The approval of the first HIV-1 protease inhibitors (HIV-1 PRIs) marked a fundamental step in the control of AIDS, and this class of agents still represents the mainstay therapy for this illness. Despite the undisputed benefits, the necessary lifelong treatment led to numerous severe side-effects (metabolic syndrome, hepatotoxicity, diabetes, etc.). The HIV-1 PRIs are capable of interacting with \u201csecondary\u201d targets (off-targets) characterized by different biological activities from that of HIV-1 protease. In this scenario, the in-silico techniques undoubtedly contributed to the design of new small molecules with well-fitting selectivity against the main target, analyzing possible undesirable interactions that are already in the early stages of the research process. The present work is focused on a new mixed-hierarchical, ligand-structure-based protocol, which is centered on an on\/off-target approach, to identify the new selective inhibitors of HIV-1 PR. The use of the well-established, ligand-based tools available in the DRUDIT web platform, in combination with a conventional, structure-based molecular docking process, permitted to fast screen a large database of active molecules and to select a set of structure with optimal on\/off-target profiles. Therefore, the method exposed herein, could represent a reliable help in the research of new selective targeted small molecules, permitting to design new agents without undesirable interactions.<\/jats:p>","DOI":"10.3390\/ijms22116070","type":"journal-article","created":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T11:12:13Z","timestamp":1622805133000},"page":"6070","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Off-Target-Based Design of Selective HIV-1 PROTEASE Inhibitors"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6510-1943","authenticated-orcid":false,"given":"Gabriele","family":"La Monica","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche \u201cSTEBICEF\u201d, Universit\u00e0 degli Studi di Palermo, Viale delle Scienze\u2014Ed, 17-90128 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5116-6815","authenticated-orcid":false,"given":"Antonino","family":"Lauria","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche \u201cSTEBICEF\u201d, Universit\u00e0 degli Studi di Palermo, Viale delle Scienze\u2014Ed, 17-90128 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9283-4920","authenticated-orcid":false,"given":"Alessia","family":"Bono","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche \u201cSTEBICEF\u201d, Universit\u00e0 degli Studi di Palermo, Viale delle Scienze\u2014Ed, 17-90128 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9560-1882","authenticated-orcid":false,"given":"Annamaria","family":"Martorana","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche \u201cSTEBICEF\u201d, Universit\u00e0 degli Studi di Palermo, Viale delle Scienze\u2014Ed, 17-90128 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.virol.2015.03.021","article-title":"Retroviral proteases and their roles in virion maturation","volume":"479\u2013480","author":"Konvalinka","year":"2015","journal-title":"Virology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/jmbi.1998.2354","article-title":"Structural biology of HIV","volume":"285","author":"Turner","year":"1999","journal-title":"J. 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