Flap-site fragment restores back wild-type behaviour in resistant form of HIV protease

HIV-1 protease (HIV-PR) performs a vital step in the virus life cycle which makes it an excellent target for drug therapy. However, due to the error-prone of HIV reverse transcriptase, mutations in HIV-PR often occur, inducing drug-resistance to inhibitors. Some HIV-PR mutations can make the flaps o...

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Autores principales: Luchi, Adriano Martín, Angelina, Emilio Luis, Bogado, María Lucrecia, Forli, Stefano, Olson, Arthur, Peruchena, Nélida María
Formato: Artículo
Lenguaje:Inglés
Publicado: Wiley Online Library 2025
Materias:
AIDS
Allosteric inhibitor
Molecular dynamics
Principal component analysis
QTAIM
Acceso en línea:http://repositorio.unne.edu.ar/handle/123456789/56523
Aporte de:
RIUNNE - Repositorio Institucional de la Universidad Nacional del Nordeste (UNNE) de Universidad Nacional del Nordeste
id I48-R184-123456789-56523
record_format dspace
spelling I48-R184-123456789-565232025-04-25T23:07:55Z Flap-site fragment restores back wild-type behaviour in resistant form of HIV protease Luchi, Adriano Martín Angelina, Emilio Luis Bogado, María Lucrecia Forli, Stefano Olson, Arthur Peruchena, Nélida María AIDS Allosteric inhibitor Molecular dynamics Principal component analysis QTAIM HIV-1 protease (HIV-PR) performs a vital step in the virus life cycle which makes it an excellent target for drug therapy. However, due to the error-prone of HIV reverse transcriptase, mutations in HIV-PR often occur, inducing drug-resistance to inhibitors. Some HIV-PR mutations can make the flaps of the enzyme more flexible thus increasing the flaps opening rate and inhibitor releasing. It has been shown that by targeting novel binding sites on HIV-PR with small molecules, it is possible to alter the equilibrium of flap conformational states. A previous frag-ment-based crystallographic screen have found two novel binding sites for small fragments in the inhibited, closed form of HIV-PR, termed flap and exo sites. While these experiments were performed in wild type HIV-PR, it still remains to be proven whether these small fragments can stabilize the closed conformation of flaps in resistant forms of the enzyme. Here we performed Molecular Dynamics simulations of wild type and mutant form of HIV-PR bound to inhibitor TL-3. Simulations show that on going from wild type to 6X mutant the equilibrium shifts from closed to semi-open conformation of flaps. However, fragment Br6 is placed at flap site of mutant form, the enzyme is restored back to closed conformation. This finding supports the hypothesis that allosteric inhibitors, together with active site inhibitors could increase the number of point mutations necessary for appreciable clinical resistance to AIDS therapy. 2025-04-16T14:08:57Z 2025-04-16T14:08:57Z 2018 Artículo Luchi, Adriano Martín, et al., 2018. Flap-site fragment restores back wild-type behaviour in resistant form of HIV protease. Molecular Informatics. Weinheim: Wiley Online Library, vol. 37, no. 12, p. 1-10. E-ISSN 1868-1751. http://repositorio.unne.edu.ar/handle/123456789/56523 eng https://onlinelibrary.wiley.com/doi/epdf/10.1002/minf.201800053 openAccess http://creativecommons.org/licenses/by-nc-nd/2.5/ar/ application/pdf p. 1-10 application/pdf Wiley Online Library Molecular Informatics, 2018, vol. 37, no. 12, p. 1-10.
institution Universidad Nacional del Nordeste
institution_str I-48
repository_str R-184
collection RIUNNE - Repositorio Institucional de la Universidad Nacional del Nordeste (UNNE)
language Inglés
topic AIDS
Allosteric inhibitor
Molecular dynamics
Principal component analysis
QTAIM
spellingShingle AIDS
Allosteric inhibitor
Molecular dynamics
Principal component analysis
QTAIM
Luchi, Adriano Martín
Angelina, Emilio Luis
Bogado, María Lucrecia
Forli, Stefano
Olson, Arthur
Peruchena, Nélida María
Flap-site fragment restores back wild-type behaviour in resistant form of HIV protease
topic_facet AIDS
Allosteric inhibitor
Molecular dynamics
Principal component analysis
QTAIM
description HIV-1 protease (HIV-PR) performs a vital step in the virus life cycle which makes it an excellent target for drug therapy. However, due to the error-prone of HIV reverse transcriptase, mutations in HIV-PR often occur, inducing drug-resistance to inhibitors. Some HIV-PR mutations can make the flaps of the enzyme more flexible thus increasing the flaps opening rate and inhibitor releasing. It has been shown that by targeting novel binding sites on HIV-PR with small molecules, it is possible to alter the equilibrium of flap conformational states. A previous frag-ment-based crystallographic screen have found two novel binding sites for small fragments in the inhibited, closed form of HIV-PR, termed flap and exo sites. While these experiments were performed in wild type HIV-PR, it still remains to be proven whether these small fragments can stabilize the closed conformation of flaps in resistant forms of the enzyme. Here we performed Molecular Dynamics simulations of wild type and mutant form of HIV-PR bound to inhibitor TL-3. Simulations show that on going from wild type to 6X mutant the equilibrium shifts from closed to semi-open conformation of flaps. However, fragment Br6 is placed at flap site of mutant form, the enzyme is restored back to closed conformation. This finding supports the hypothesis that allosteric inhibitors, together with active site inhibitors could increase the number of point mutations necessary for appreciable clinical resistance to AIDS therapy.
format Artículo
author Luchi, Adriano Martín
Angelina, Emilio Luis
Bogado, María Lucrecia
Forli, Stefano
Olson, Arthur
Peruchena, Nélida María
author_facet Luchi, Adriano Martín
Angelina, Emilio Luis
Bogado, María Lucrecia
Forli, Stefano
Olson, Arthur
Peruchena, Nélida María
author_sort Luchi, Adriano Martín
title Flap-site fragment restores back wild-type behaviour in resistant form of HIV protease
title_short Flap-site fragment restores back wild-type behaviour in resistant form of HIV protease
title_full Flap-site fragment restores back wild-type behaviour in resistant form of HIV protease
title_fullStr Flap-site fragment restores back wild-type behaviour in resistant form of HIV protease
title_full_unstemmed Flap-site fragment restores back wild-type behaviour in resistant form of HIV protease
title_sort flap-site fragment restores back wild-type behaviour in resistant form of hiv protease
publisher Wiley Online Library
publishDate 2025
url http://repositorio.unne.edu.ar/handle/123456789/56523
work_keys_str_mv AT luchiadrianomartin flapsitefragmentrestoresbackwildtypebehaviourinresistantformofhivprotease
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AT bogadomarialucrecia flapsitefragmentrestoresbackwildtypebehaviourinresistantformofhivprotease
AT forlistefano flapsitefragmentrestoresbackwildtypebehaviourinresistantformofhivprotease
AT olsonarthur flapsitefragmentrestoresbackwildtypebehaviourinresistantformofhivprotease
AT peruchenanelidamaria flapsitefragmentrestoresbackwildtypebehaviourinresistantformofhivprotease
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