New insights into the in silico prediction of HIV protease resistance to nelfinavir.
The Human Immunodeficiency Virus type 1 protease enzyme (HIV-1 PR) is one of the most important targets of antiretroviral therapy used in the treatment of AIDS patients. The success of protease-inhibitors (PIs), however, is often limited by the emergence of protease mutations that can confer resistance to a specific drug, or even to multiple PIs. In the present study, we used bioinformatics tools to evaluate the impact of the unusual mutations D30V and V32E over the dynamics of the PR-Nelfinavir complex, considering that codons involved in these mutations were previously related to major drug resistance to Nelfinavir. Both studied mutations presented structural features that indicate resistance to Nelfinavir, each one with a different impact over the interaction with the drug. The D30V mutation triggered a subtle change in the PR structure, which was also observed for the well-known Nelfinavir resistance mutation D30N, while the V32E exchange presented a much more dramatic impact over the PR flap dynamics. Moreover, our in silico approach was also able to describe different binding modes of the drug when bound to different proteases, identifying specific features of HIV-1 subtype B and subtype C proteases.
Núcleo de Bioinformática do Laboratório de Imunogenética (NBLI), Departamento de Genética, Universidade Federal do Rio Grande do Sul. Porto Alegre, Rio Grande do Sul, Brazil ; Programa de Pós-Graduação em Genética e Biologia Molecular (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.
Dinler A
DA
Antunes
Núcleo de Bioinformática do Laboratório de Imunogenética (NBLI), Departamento de Genética, Universidade Federal do Rio Grande do Sul. Porto Alegre, Rio Grande do Sul, Brazil ; Programa de Pós-Graduação em Genética e Biologia Molecular (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.
Maurício M
MM
Rigo
Núcleo de Bioinformática do Laboratório de Imunogenética (NBLI), Departamento de Genética, Universidade Federal do Rio Grande do Sul. Porto Alegre, Rio Grande do Sul, Brazil ; Programa de Pós-Graduação em Genética e Biologia Molecular (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.
Marialva
M
Sinigaglia
Technological and Scientific Development Center (CDCT), State Foundation in Production and Health Research (FEPPS), Porto Alegre, Rio Grande do Sul, Brazil ; Programa de Pós-Graduação em Genética e Biologia Molecular (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.
Rúbia M
RM
de Medeiros
Technological and Scientific Development Center (CDCT), State Foundation in Production and Health Research (FEPPS), Porto Alegre, Rio Grande do Sul, Brazil ; Programa de Pós-Graduação em Genética e Biologia Molecular (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.
Dennis M
DM
Junqueira
Technological and Scientific Development Center (CDCT), State Foundation in Production and Health Research (FEPPS), Porto Alegre, Rio Grande do Sul, Brazil.
Sabrina E M
SE
Almeida
Núcleo de Bioinformática do Laboratório de Imunogenética (NBLI), Departamento de Genética, Universidade Federal do Rio Grande do Sul. Porto Alegre, Rio Grande do Sul, Brazil ; Programa de Pós-Graduação em Genética e Biologia Molecular (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.
Gustavo F
GF
Vieira
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D019943:Amino Acid Substitution; D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000201:enzymology / Q000235:genetics; D006801:Humans; D020125:Mutation, Missense; D019888:Nelfinavir / Q000737:chemistry*
D017320:HIV Protease Inhibitors; D016333:HIV Protease; D019888:Nelfinavir