Publicação
Computational modeling of the HIV-1 integrase enzyme
| Resumo: | The Human Immunodeficiency Virus (HIV), mainly known for its type 1 (HIV-1), continues to be one of the most alarming viral infections worldwide, with a growing prevalence in developing countries. Due to its high genetic variability and tendency to develop resistance to existing therapies, the increase in new cases over recent years has become increasingly concerning due to a potential future public health issue. In recent times, new insertions in the HIV-1 genome have been identified, some of which have been shown to be detrimental to the effectiveness of therapies, while others have no negative impact. Thus, understanding the effect of mutations in the HIV-1 genome and developing new drugs effective against potential resistance to inhibitors is crucial to public health safety. This master's thesis focuses on a case found in Portugal, where an insertion of a threonine and an asparagine between positions 255 and 256 of the C-terminal domain of HIV-1 integrase was identified in two infected individuals. Using various computational approaches, a study was conducted on the effect of this insertion on the development of resistance to bictegravir, an integrase inhibitor. These approaches include protein modeling and molecular dynamics simulation, utilizing software such as MODELLER, AutoDock Vina, CHARMM-GUI, and GROMACS. For further analysis, techniques such as RMSD, RMSF, minimum distance average, canonical correlation analysis, hydrogen bond, MMPBSA, and SASA analysis were used. |
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| Autores principais: | André, Inês dos Santos |
| Assunto: | HIV-1 integrase antiretroviral therapy drug resistance molecular dynamics HIV-1 integrase terapia antirretroviral resistência a medicamentos dinâmica molecular |
| Ano: | 2024 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso embargado |
| Instituição associada: | Universidade de Coimbra |
| Idioma: | inglês |
| Origem: | Estudo Geral - Universidade de Coimbra |
| Resumo: | The Human Immunodeficiency Virus (HIV), mainly known for its type 1 (HIV-1), continues to be one of the most alarming viral infections worldwide, with a growing prevalence in developing countries. Due to its high genetic variability and tendency to develop resistance to existing therapies, the increase in new cases over recent years has become increasingly concerning due to a potential future public health issue. In recent times, new insertions in the HIV-1 genome have been identified, some of which have been shown to be detrimental to the effectiveness of therapies, while others have no negative impact. Thus, understanding the effect of mutations in the HIV-1 genome and developing new drugs effective against potential resistance to inhibitors is crucial to public health safety. This master's thesis focuses on a case found in Portugal, where an insertion of a threonine and an asparagine between positions 255 and 256 of the C-terminal domain of HIV-1 integrase was identified in two infected individuals. Using various computational approaches, a study was conducted on the effect of this insertion on the development of resistance to bictegravir, an integrase inhibitor. These approaches include protein modeling and molecular dynamics simulation, utilizing software such as MODELLER, AutoDock Vina, CHARMM-GUI, and GROMACS. For further analysis, techniques such as RMSD, RMSF, minimum distance average, canonical correlation analysis, hydrogen bond, MMPBSA, and SASA analysis were used. |
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