Revealing the drug resistance mechanism of saquinavir due to G48V and V82F mutations in subtype CRF01_AE HIV-1 protease: molecular dynamics simulation and binding free energy calculations.
PMID: 17543558
2007
Journal of molecular graphics & modelling
Abstract: Moreover, the G48V/L90M mutations cause the repositioning of the residues close to residues 48 and 90, at important locations as a part of the flap and catalytic regions, respectively.
Abstract: The two most important HIV-1 PR mutants are G48V and G48V/L90M.
Abstract: We have found that the interaction of SQV with flap residue 48 of the mutants is significantly perturbed, as shown by the reduced stability of binding between SQV and residue 48 for the G48V and G48V/L90M mutants over the wild-type.
Insights into a mutation-assisted lateral drug escape mechanism from the HIV-1 protease active site.
Abstract: Significant inhibitor deviation is reported over 24 ns, and subsequent complete expulsion, implemented using steered molecular dynamics simulations, is shown to occur most easily for the G48V-containing mutants.
Abstract: We find a consistent escape mechanism associated with the G48V mutation.
Abstract: We provide insight into the first stages of a kinetic mechanism of lateral drug expulsion from the active site of HIV-1 protease, by conducting all atom molecular dynamics simulations with explicit solvent over a time scale of 24 ns for saquinavir bound to the wildtype, G48V, L90M and G48V/L90M mutant proteases.
Structural and dynamical properties of different protonated states of mutant HIV-1 protease complexed with the saquinavir inhibitor studied by molecular dynamics simulations.
PMID: 16504560
2006
Journal of molecular graphics & modelling
Abstract: To understand the basis of drug resistance, particularly of the HIV-1 PR, three molecular dynamics (MD) simulations of HIV-1 PR mutant species, G48V, complexed with saquinavir (SQV) in explicit aqueous solution with three protonation states, diprotonation on Asp25 and Asp25' (Di-pro) and monoprotonation on each Asp residue (Mono-25 and Mono-25').
Non-infectious fluorimetric assay for phenotyping of drug-resistant HIV proteinase mutants.
Abstract: RESULTS: We cloned a set of GFP-PR reporters, some of which possess a simple, well-defined drug-resistant PR mutant (G48V L90M, V82A, A71V V82T I84V, D30N, K45I); another four complex PR mutants were obtained from patients undergoing HAART.
Gated binding of ligands to HIV-1 protease: Brownian dynamics simulations in a coarse-grained model.
Abstract: The computed gated association rate constants of three protease mutants, G48V/V82A/I84V/L90M, G48V, and L90M with three drugs, amprenavir, indinavir, and saquinavir, yield good agreements with experiments.
Abstract: The simulations suggest that the flap flexibility and the opening frequency of the wild-type, the G48V and L90M mutants are similar, but the flaps of the variant G48V/V82A/I84V/L90M open less frequently, resulting in a lower gated rate constant.
Evidence of differential selection of HIV-1 variants carrying drug-resistant mutations in seroconverters.
Abstract: Among the mutations not detected in viruses from SCs, the RT E44D, V1081, Q151M and Y188C/H/L, and the protease D30N, G48V and V82A/F/S/T substitutions appeared to be negatively selected.
Temporal characterization of drug resistance associated mutations in HIV-1 protease and reverse transcriptase in patients failing antiretroviral therapy.
Abstract: From 1999 to 2003, resistance-mutations to drugs with high genetic-barrier significantly decreased (L90M/V82A/M46I/I54V/G73S/I84V/G48V for PIs; M41L/D67N/L210W/V1181 for NRTIs, p < 0.05), while mutations to drugs with low genetic-barrier increased (D30N in protease, M184V/K103N/V108I in reverse transcriptase, p < 0.05).
Revealing the drug resistance mechanism of saquinavir due to G48V and V82F mutations in subtype CRF01_AE HIV-1 protease: molecular dynamics simulation and binding free energy calculations.
Abstract: Molecular dynamics simulations of the wild-type and the G48V HIV-1 protease complexed with saquinavir were carried out to explore structure and interactions of the drug resistance.
Abstract: The G48V is considered the key signature residue mutation of HIV-1 protease developing with saquinavir therapy.
Characterization of mutations in CRF01_AE virus isolates from antiretroviral treatment-naive and -experienced patients in Singapore.
PMID: 15608517
2005
Journal of acquired immune deficiency syndromes (1999)
Abstract: There were differences between CRF01_AE and subtype B viruses in several drug resistance mutations including the following: D67N, L210F, K101E, V106M, V179I/D, G190A/S/E, and G48V (which were more common in CRF01_AE virus) and M41L, T215Y, and V82A (which were less common in CRF01_AE virus).
HIV mutation literature information.
PMID: 
2007
PLoS computational biology
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