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Revealing origin of decrease in potency of darunavir and amprenavir against HIV-2 relative to HIV-1 protease by molecular dynamics simulations.

Chen J, Liang Z, Wang W, Yi C, Zhang S, Zhang Q - Sci Rep (2014)

Bottom Line: To identify molecular basis associated with the lower inhibition, molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations were performed to investigate the effectiveness of the PR1 inhibitors DRV and APV against PR1/PR2.The decrease in binding free energies for PR2 relative to PR1 is found to arise from the reduction of the van der Waals interactions induced by the structural adjustment of the triple mutant V32I, I47V and V82I.We expect that this study can theoretically provide significant guidance and dynamics information for the design of potent dual inhibitors targeting PR1/PR2.

View Article: PubMed Central - PubMed

Affiliation: School of Science, Shandong Jiaotong University, Jinan 250357, China.

ABSTRACT
Clinical inhibitors Darunavir (DRV) and Amprenavir (APV) are less effective on HIV-2 protease (PR2) than on HIV-1 protease (PR1). To identify molecular basis associated with the lower inhibition, molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations were performed to investigate the effectiveness of the PR1 inhibitors DRV and APV against PR1/PR2. The rank of predicted binding free energies agrees with the experimental determined one. Moreover, our results show that two inhibitors bind less strongly to PR2 than to PR1, again in agreement with the experimental findings. The decrease in binding free energies for PR2 relative to PR1 is found to arise from the reduction of the van der Waals interactions induced by the structural adjustment of the triple mutant V32I, I47V and V82I. This result is further supported by the difference between the van der Waals interactions of inhibitors with each residue in PR2 and in PR1. The results from the principle component analysis suggest that inhibitor binding tends to make the flaps of PR2 close and the one of PR1 open. We expect that this study can theoretically provide significant guidance and dynamics information for the design of potent dual inhibitors targeting PR1/PR2.

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Comparison of PR1 and PR2 interactions with APV.The structure is colored by atom type, the groups of APV are shown in ball and stick mode, and the residues shown in stick mode. (A)–(D) represent the interactions between the hydrophobic groups of APPV and key residues of PR1, (E)–(H) show the interactions between the hydrophobic groups of APV and key residues of PR2.
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f9: Comparison of PR1 and PR2 interactions with APV.The structure is colored by atom type, the groups of APV are shown in ball and stick mode, and the residues shown in stick mode. (A)–(D) represent the interactions between the hydrophobic groups of APPV and key residues of PR1, (E)–(H) show the interactions between the hydrophobic groups of APV and key residues of PR2.

Mentions: Figure 7 gives the difference between the van der Waals interactions of two inhibitors with each residue in PR2 and in PR1. Figure 8 and 9 depict the geometrical positions of three mutated residues relative to the key hydrophobic groups of two inhibitors based on the lowest-energy structure from MD trajectory. As shown in Figure 7A, the van der Waals interactions of the mutated residues V32I, I47V, V32′I and I47′V in PR2 with DRV are decreased by 0.49, 0.86, 0.69 and 0.26 kcal·mol−1 compared to PR1, respectively. This result agrees well with the structural descriptions in Figure 8A, B, E and F. By comparisons of Figure 8E and F with Figure 8A and B, it is found that the distances of the key carbon atoms between these four mutated residues in PR2 and the aniline and bis-THF of DRV are increased, which in turn weaken the CH-π interactions of the alkyls in four mutated residues with the aniline and bis-THF. Additionally, the van der Waals interactions of the residues I50 and D29′ in PR2 with DRV are also reduced relative to PR1. Figure 7A suggests that the mutation V82I strengthens the van der Walls interaction with DRV, which is in agreement with the shortened distance between the carbon atoms in phenyl of DRV and the alkyl of V82I in PR2 (Figure 8C and G). By comparing Figure 8H to D, one can see that the distances between the carbon atoms of the alkyls in V82′I of PR2 and DRV are reduced, which correspondingly produces an increase of 0.47 kcal·mol−1 in the van der Waals interactions. In addition, the van der Waals interactions of the residues G48, D30′ and G49′ in PR2 with DRV are also strengthened compared to PR1 (Figure 7A).


Revealing origin of decrease in potency of darunavir and amprenavir against HIV-2 relative to HIV-1 protease by molecular dynamics simulations.

Chen J, Liang Z, Wang W, Yi C, Zhang S, Zhang Q - Sci Rep (2014)

Comparison of PR1 and PR2 interactions with APV.The structure is colored by atom type, the groups of APV are shown in ball and stick mode, and the residues shown in stick mode. (A)–(D) represent the interactions between the hydrophobic groups of APPV and key residues of PR1, (E)–(H) show the interactions between the hydrophobic groups of APV and key residues of PR2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4217091&req=5

f9: Comparison of PR1 and PR2 interactions with APV.The structure is colored by atom type, the groups of APV are shown in ball and stick mode, and the residues shown in stick mode. (A)–(D) represent the interactions between the hydrophobic groups of APPV and key residues of PR1, (E)–(H) show the interactions between the hydrophobic groups of APV and key residues of PR2.
Mentions: Figure 7 gives the difference between the van der Waals interactions of two inhibitors with each residue in PR2 and in PR1. Figure 8 and 9 depict the geometrical positions of three mutated residues relative to the key hydrophobic groups of two inhibitors based on the lowest-energy structure from MD trajectory. As shown in Figure 7A, the van der Waals interactions of the mutated residues V32I, I47V, V32′I and I47′V in PR2 with DRV are decreased by 0.49, 0.86, 0.69 and 0.26 kcal·mol−1 compared to PR1, respectively. This result agrees well with the structural descriptions in Figure 8A, B, E and F. By comparisons of Figure 8E and F with Figure 8A and B, it is found that the distances of the key carbon atoms between these four mutated residues in PR2 and the aniline and bis-THF of DRV are increased, which in turn weaken the CH-π interactions of the alkyls in four mutated residues with the aniline and bis-THF. Additionally, the van der Waals interactions of the residues I50 and D29′ in PR2 with DRV are also reduced relative to PR1. Figure 7A suggests that the mutation V82I strengthens the van der Walls interaction with DRV, which is in agreement with the shortened distance between the carbon atoms in phenyl of DRV and the alkyl of V82I in PR2 (Figure 8C and G). By comparing Figure 8H to D, one can see that the distances between the carbon atoms of the alkyls in V82′I of PR2 and DRV are reduced, which correspondingly produces an increase of 0.47 kcal·mol−1 in the van der Waals interactions. In addition, the van der Waals interactions of the residues G48, D30′ and G49′ in PR2 with DRV are also strengthened compared to PR1 (Figure 7A).

Bottom Line: To identify molecular basis associated with the lower inhibition, molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations were performed to investigate the effectiveness of the PR1 inhibitors DRV and APV against PR1/PR2.The decrease in binding free energies for PR2 relative to PR1 is found to arise from the reduction of the van der Waals interactions induced by the structural adjustment of the triple mutant V32I, I47V and V82I.We expect that this study can theoretically provide significant guidance and dynamics information for the design of potent dual inhibitors targeting PR1/PR2.

View Article: PubMed Central - PubMed

Affiliation: School of Science, Shandong Jiaotong University, Jinan 250357, China.

ABSTRACT
Clinical inhibitors Darunavir (DRV) and Amprenavir (APV) are less effective on HIV-2 protease (PR2) than on HIV-1 protease (PR1). To identify molecular basis associated with the lower inhibition, molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations were performed to investigate the effectiveness of the PR1 inhibitors DRV and APV against PR1/PR2. The rank of predicted binding free energies agrees with the experimental determined one. Moreover, our results show that two inhibitors bind less strongly to PR2 than to PR1, again in agreement with the experimental findings. The decrease in binding free energies for PR2 relative to PR1 is found to arise from the reduction of the van der Waals interactions induced by the structural adjustment of the triple mutant V32I, I47V and V82I. This result is further supported by the difference between the van der Waals interactions of inhibitors with each residue in PR2 and in PR1. The results from the principle component analysis suggest that inhibitor binding tends to make the flaps of PR2 close and the one of PR1 open. We expect that this study can theoretically provide significant guidance and dynamics information for the design of potent dual inhibitors targeting PR1/PR2.

Show MeSH