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Off-Target-Based Design of Selective HIV-1 PROTEASE Inhibitors

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 (m...

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Autores principales: Monica, Gabriele La, Lauria, Antonino, Bono, Alessia, Martorana, Annamaria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200130/
https://www.ncbi.nlm.nih.gov/pubmed/34199858
http://dx.doi.org/10.3390/ijms22116070
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author Monica, Gabriele La
Lauria, Antonino
Bono, Alessia
Martorana, Annamaria
author_facet Monica, Gabriele La
Lauria, Antonino
Bono, Alessia
Martorana, Annamaria
author_sort Monica, Gabriele La
collection PubMed
description 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 “secondary” 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.
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spelling pubmed-82001302021-06-14 Off-Target-Based Design of Selective HIV-1 PROTEASE Inhibitors Monica, Gabriele La Lauria, Antonino Bono, Alessia Martorana, Annamaria Int J Mol Sci Article 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 “secondary” 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. MDPI 2021-06-04 /pmc/articles/PMC8200130/ /pubmed/34199858 http://dx.doi.org/10.3390/ijms22116070 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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/licenses/by/4.0/).
spellingShingle Article
Monica, Gabriele La
Lauria, Antonino
Bono, Alessia
Martorana, Annamaria
Off-Target-Based Design of Selective HIV-1 PROTEASE Inhibitors
title Off-Target-Based Design of Selective HIV-1 PROTEASE Inhibitors
title_full Off-Target-Based Design of Selective HIV-1 PROTEASE Inhibitors
title_fullStr Off-Target-Based Design of Selective HIV-1 PROTEASE Inhibitors
title_full_unstemmed Off-Target-Based Design of Selective HIV-1 PROTEASE Inhibitors
title_short Off-Target-Based Design of Selective HIV-1 PROTEASE Inhibitors
title_sort off-target-based design of selective hiv-1 protease inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200130/
https://www.ncbi.nlm.nih.gov/pubmed/34199858
http://dx.doi.org/10.3390/ijms22116070
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