The current strategy to improve the quality of life of Human Immunodeficiency Virus (HIV) infected individuals through suppressing viral replication and maintaining the virus at low to undetectable levels is based on highly active antiretroviral therapy (HAART). Protease inhibitors are essential components of most HAART protocols and are often used as the first line of treatment. However, a considerable percentage of new HIV-1 infections are caused by viruses carrying anti retroviral drug-resistant mutations. In this paper molecular dynamics, docking simulations, and free energy analysis of mutated HIV protease complexes were used to estimate the influence of different drug resistance-associated mutations in lopinavir, amprenavir, saquinavir, and atazanavir protease recognition. In agreement with virological and clinical data, the structural analysis showed that the single mutations V82A, I84V, and M461 are associated with higher energetic values for all analyzed complexes with respect to wild-type, indicating their decreased stability. Interestingly, in atazanavir complexes, in the presence of the L76V substitution, the drug revealed a more productive binding affinity, in agreement with hypersusceptibility data.

Alcaro, S., Artese, A., CECCHERINI SILBERSTEIN, F., Ortuso, F., Perno, C.f., Sing, T., et al. (2009). Molecular dynamics and free energy studies on the wild-type and mutated hiv-1 protease complexed with four approved drugs: Mechanism of binding and drug resistance, 49(7), 1751-1761 [10.1021/ci900012k].

Molecular dynamics and free energy studies on the wild-type and mutated hiv-1 protease complexed with four approved drugs: Mechanism of binding and drug resistance

CECCHERINI SILBERSTEIN, FRANCESCA;PERNO, CARLO FEDERICO;SVICHER, VALENTINA
2009-01-01

Abstract

The current strategy to improve the quality of life of Human Immunodeficiency Virus (HIV) infected individuals through suppressing viral replication and maintaining the virus at low to undetectable levels is based on highly active antiretroviral therapy (HAART). Protease inhibitors are essential components of most HAART protocols and are often used as the first line of treatment. However, a considerable percentage of new HIV-1 infections are caused by viruses carrying anti retroviral drug-resistant mutations. In this paper molecular dynamics, docking simulations, and free energy analysis of mutated HIV protease complexes were used to estimate the influence of different drug resistance-associated mutations in lopinavir, amprenavir, saquinavir, and atazanavir protease recognition. In agreement with virological and clinical data, the structural analysis showed that the single mutations V82A, I84V, and M461 are associated with higher energetic values for all analyzed complexes with respect to wild-type, indicating their decreased stability. Interestingly, in atazanavir complexes, in the presence of the L76V substitution, the drug revealed a more productive binding affinity, in agreement with hypersusceptibility data.
2009
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA
English
Con Impact Factor ISI
Antiretroviral drugs; Binding affinities; Clinical data; Docking simulations; Drug resistance; Energetic value; Essential component; Free energy analysis; Highly active anti-retroviral therapies; HIV-1 infections; HIV-1 protease; HIV-protease; Human immunodeficiency virus; Protease inhibitor; Quality of life; Saquinavir; Single mutation; Viral replication; Wild types; Energy management; Enzyme inhibition; Free energy; Molecular dynamics; Structural analysis; Binding energy; p16 protease, Human immunodeficiency virus 1; proteinase; proteinase inhibitor; antiviral resistance; article; chemical structure; chemistry; computer simulation; enzymology; genetics; human; Human immunodeficiency virus 1; metabolism; point mutation; protein binding; protein conformation; thermodynamics; X ray crystallography; Computer Simulation; Crystallography, X-Ray; Drug Resistance, Viral; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Models, Molecular; Molecular Structure; Point Mutation; Protein Binding; Protein Conformation; Thermodynamics
Alcaro, S., Artese, A., CECCHERINI SILBERSTEIN, F., Ortuso, F., Perno, C.f., Sing, T., et al. (2009). Molecular dynamics and free energy studies on the wild-type and mutated hiv-1 protease complexed with four approved drugs: Mechanism of binding and drug resistance, 49(7), 1751-1761 [10.1021/ci900012k].
Alcaro, S; Artese, A; CECCHERINI SILBERSTEIN, F; Ortuso, F; Perno, Cf; Sing, T; Svicher, V
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/47250
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