A contribution to the drug resistance mechanism of darunavir, amprenavir, indinavir, and saquinavir complexes with HIV-1 protease due to flap mutation I50V: a systematic MM-PBSA and thermodynamic integration study.
PMID: 23834142
2013
Journal of chemical information and modeling
Abstract: Conformational analysis showed that the protease flaps are increasingly flexible in the I50V complexes.
Abstract: Thermodynamic integration calculations reproduced the experimental data to within1 kcal mol-1 and showed that the I50V mutation results in weaker binding free energies for all analyzed complexes with respect to the WT.
Abstract: This computational comparative study contributes toward elucidation of the I50V drug-resistance mechanism in HIV-1 PR.
Abstract: This predicts that I50V may confer low resistance to 3c.
Abstract: Upon I50V mutation, the complex binding free energy was weakened by a DeltaDeltaG(TI) of 1.8 kcal mol-1, comparable to the marketed inhibitors.
Abstract: We employed molecular dy
Trends in Genotypic HIV-1 Antiretroviral Resistance between 2006 and 2012 in South African Patients Receiving First- and Second-Line Antiretroviral Treatment Regimens.
Method: The following non-polymorphic ARV-selected mutations were classified as drug resistance mutations (DRM): (i) the NRTI resistance mutations M41L, A62V, K65RN, D67NG, T69D, T69 insertions, T69 deletion, K70REGQ, L74VI, V75MT, F77L, Y115F, F116Y, Q151M, M184VI, L210W, T215YFSDCIV, and K219QENR; (ii) the
Persistence of HIV-1 transmitted drug resistance mutations.
PMID: 23904291
2013
The Journal of infectious diseases
Table: I50 V
Increasing trends in primary NNRTI resistance among newly HIV-1-diagnosed individuals in Buenos Aires, Argentina.
PMID: 24093951
2013
Journal of the International AIDS Society
Method: Sequences were analyzed to identify mutations associated with reduced susceptibility to protease and RT inhibitors, as reported by the International AIDS Society-USA in 2010: RT-M41L, A62V, K65R, D67N, 69 insert, K70R, L74V,V75I, F77L, L100I, K101P, K103N, V106A, V106M, V108I, Y115F, F116Y,
Virological response to darunavir in patients infected with HIV is linked to darunavir resistance-associated mutations corrected by the count of mutations with positive impact and is not associated with pharmacological and combined virological/pharmacological parameters.
PMID: 21545648
2012
Fundamental & clinical pharmacology
Abstract: Darunavir GIQ is defined as the ratio between darunavir trough plasma concentration and the count of darunavir resistance-associated mutations (V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, I84V, L89V) corrected or not corrected by the count of mutations with positive impact (V82A and E35D).
Interpretation of genotypic resistance to predict darunavir/ritonavir failure in antiretroviral experienced patients.
PMID: 22067663
2012
Journal of acquired immune deficiency syndromes (1999)
Abstract: Four mutations (V32I, I50V, L76V, I84V) were predictive of failure, the hazard ratio progressively increased by detecting 1 (hazard ratio: 2.0, 95% confidence interval: 1.3 to 3.0), 2 (3.6, 2.0 to 6.6), or 3 of them (9.7, 2.8 to 33.5).
Genotypic resistance profiles associated with virological failure to darunavir-containing regimens: a cross-sectional analysis.
Abstract: At DRV failure, the major increase was still observed for V32I; I54L, V11I, T74P and I50V also increased.
A Comparative Molecular Dynamics, MM-PBSA and Thermodynamic Integration Study of Saquinavir Complexes with Wild-Type HIV-1 PR and L10I, G48V, L63P, A71V, G73S, V82A and I84V Single Mutants.
PMID: 22239286
2012
The journal of physical chemistry. B
Abstract: As for the other previous studies, the present results also show that the single mutant I50V decreases the binding affinity of I50V-HIV-pr to TMC, resulting in a drug resistance; whereas the double mutant I50L/A71V increases the binding affinity, and as a result of the stronger binding, the I50L/A71V may be well adapted by the TMC114.
Abstract: For example, the flap-flap distance and the distance from the active site to the flap residues in the apo I50L/A71V-HIV-pr are smaller than those of WT- and I50V-HIV-pr, probably making the active site smaller in volume and closer
Interaction of I50V mutant and I50L/A71V double mutant HIV-protease with inhibitor TMC114 (darunavir): molecular dynamics simulation and binding free energy studies.
PMID: 22239286
2012
The journal of physical chemistry. B
Result: As shown in Table 1, the experimental binding affinity difference between WT and I50V-HIV was 1.3-3.30 kcal/mol, which was determined to induce rather different performance to the TMC.
Result: For the double mutant, the distribution has one peak around 6 A, whereas for WT and I50V mutant the main peak locates around 6 A, and the other minor around 7-8 A region.
Result: From the time series plot of distance between Asp25 OD1-TMC O18 (Figure 12), it was found to be almost always constant for WT (mean of 2.64 A) and I50V (mean of 2.72 A) as compared to their initial crystal structure distance of 2.58 A and 2.59 A, respectively.
Result: Hence, on the basis of above structural energetic analysis discussed, we can conclude that the direct effects from Val50 and Val50', e.g., the decrease in van der Waals for both residues and the increa
Energetic basis for drug resistance of HIV-1 protease mutants against amprenavir.
PMID: 22350569
2012
Journal of computer-aided molecular design
Abstract: Drug resistance arises from an increase in the energetic contribution from the van der Waals interactions between APV and PR (V32I, I50V, and I84V mutant) or a rise in the energetic contribution from the electrostatic interactions between the inhibitor and its target (I54M and I54V mutant).
Abstract: However, the affinities of the drug resistant protease variants V32I, I50V, I54V, I54M, I84V and L90M to amprenavir are decreased 3 to 30-fold compared to the wild-type.
HIV mutation literature information.
PMID: 
2013
Journal of chemical information and modeling
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