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

Tzoupis, Haralambos; Leonis, Georgios; Mavromoustakos, Thomas; Παπαδόπουλος, Μάνθος Γ.

doi:10.1021/ct301063k

Cited by 52 publications

(71 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Indeed, the distance between the flap tips in the HIV PR complexes lies within ∼6–10 Å (Figure ). This suggests closed structures for the bound forms of the protease, a result that is in agreement with previous studies on similar systems . The 4 –HIV PR complex has the highest values of flap separation, which reach ∼10 Å; however, 4 is firmly anchored into the binding cavity of HIV PR during the entire simulation and it appears that a distance of 9–10 Å between flaps does not induce an open structure of the protease.…”

Section: Resultssupporting

confidence: 90%

See 1 more Smart Citation

Discovery of HIV Type 1 Aspartic Protease Hit Compounds through Combined Computational Approaches

et al. 2016

Self Cite

View full text Add to dashboard Cite

A combination of computational techniques and inhibition assay experiments was employed to identify hit compounds from commercial libraries with enhanced inhibitory potency against HIV type 1 aspartic protease (HIV PR). Extensive virtual screening with the aid of reliable pharmacophore models yielded five candidate protease inhibitors. Subsequent molecular dynamics and molecular mechanics Poisson-Boltzmann surface area free-energy calculations for the five ligand-HIV PR complexes suggested a high stability of the systems through hydrogen-bond interactions between the ligands and the protease's flaps (Ile50/50'), as well as interactions with residues of the active site (Asp25/25'/29/29'/30/30'). Binding-energy calculations for the three most promising compounds yielded values between -5 and -10 kcal mol(-1) and suggested that van der Waals interactions contribute most favorably to the total energy. The predicted binding-energy values were verified by in vitro inhibition assays, which showed promising results in the high nanomolar range. These results provide structural considerations that may guide further hit-to-lead optimization toward improved anti-HIV drugs.

show abstract

Section: Resultssupporting

confidence: 90%

“…Previous studies from our group have suggested that increased binding affinity for HIV PR is also observed if van der Waals interactions between the inhibitor and PR are significantly enhanced . In agreement with this observation, Ghosh et al .…”

Section: Introductionsupporting

confidence: 59%

Discovery of HIV Type 1 Aspartic Protease Hit Compounds through Combined Computational Approaches

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Regarding the comparative performance of MM/PBSA and MM/GBSA, our results revealed that relative binding free energy estimates obtained by MM/PBSA showed a better correlation with experimental values ( r 2 = 0.73) compared to MM/GBSA ( r 2 = 0.47), thus evidencing a slightly better performance of MM/PBSA over MM/GBSA in the particular systems under study (Figure ). This result can be explained in terms of PB being more theoretically rigorous than GB despite that MM/GBSA has shown better performance in several systems, as reported in the literature . Consequently, we have concluded that both MM/PBSA and MM/GBSA are capable of reproducing the relative binding free energy trends in E‐selectin–oligosaccharide complexes with relatively low computational cost and acceptable accuracy.…”

Section: Resultssupporting

confidence: 68%

Binding free energy calculations on E‐selectin complexes with sLe^x oligosaccharide analogs

et al. 2016

View full text Add to dashboard Cite

Molecular dynamics simulations and binding free energy calculations were employed to examine the interaction between E-selectin and six structurally related oligosaccharides including the physiological ligand sialyl Lewis x. Molecular dynamics simulations revealed that sialyl Lewis x and its mimics share a common binding region and similar interactions with E-selectin involving the formation of hydrogen bonds with Glu80, Asn82, Asn83, Arg97, Asn105, Asp106, and Glu107 residues and electrostatic contacts with Ca and the positively charged Lys111 and Lys 113 residues. Regarding binding free energy calculations, the performance of the rigorous but computationally expensive pathway methods TI, BAR, and MBAR was compared to the less rigorous but faster end-point methods MM/PBSA and MM/GBSA aimed at identifying a suitable approach to deal with the very subtle binding free energy differences within the ligands under study. All methods succeeded in predicting increased binding affinities for sialyl Lewis x analogs compared to the native ligand with absolute errors <1 kcal/mol. The best correlation with experimental data was obtained by TI (r = 0.84), followed by MBAR (r = 0.80), BAR (r = 0.73), MM/PBSA (r = 0.73) and MM/GBSA (r = 0.47). These results provide valuable information to increase understanding about E-selectin-oligosaccharide interactions and conduct further research aimed at designing novel ligands targeting this protein.

show abstract

“…The protease dimer is in dynamic equilibrium between the closed conformation and various open conformational states [7]. Molecular dynamics studies suggest that mutations in the flaps or even in distal regions may affect the flap dynamics and hence the binding of PIs [8–9]. …”

Section: Introductionmentioning

confidence: 99%

Structural Studies of a Rationally Selected Multi-Drug Resistant HIV-1 Protease Reveal Synergistic Effect of Distal Mutations on Flap Dynamics

et al. 2016

View full text Add to dashboard Cite

We report structural analysis of HIV protease variant PRS17 which was rationally selected by machine learning to represent wide classes of highly drug-resistant variants. Crystal structures were solved of PRS17 in the inhibitor-free form and in complex with antiviral inhibitor, darunavir. Despite its 17 mutations, PRS17 has only one mutation (V82S) in the inhibitor/substrate binding cavity, yet exhibits high resistance to all clinical inhibitors. PRS17 has none of the major mutations (I47V, I50V, I54ML, L76V and I84V) associated with darunavir resistance, but has 10,000-fold weaker binding affinity relative to the wild type PR. Comparable binding affinity of 8000-fold weaker than PR is seen for drug resistant mutant PR20, which bears 3 mutations associated with major resistance to darunavir (I47V, I54L and I84V). Inhibitor-free PRS17 shows an open flap conformation with a curled tip correlating with G48V flap mutation. NMR studies on inactive PRS17 D25N unambiguously confirm that the flaps adopt mainly an open conformation in solution very similar to that in the inhibitor-free crystal structure. In PRS17, the hinge loop cluster of mutations, E35D, M36I and S37D, contributes to the altered flap dynamics by a mechanism similar to that of PR20. An additional K20R mutation anchors an altered conformation of the hinge loop. Flap mutations M46L and G48V in PRS17/DRV complex alter the Phe53 conformation by steric hindrance between the side chains. Unlike the L10F mutation in PR20, L10I in PRS17 does not break the inter-subunit ion pair or diminish the dimer stability, consistent with a very low dimer dissociation constant comparable to that of wild type PR. Distal mutations A71V, L90M and I93L propagate alterations to the catalytic site of PRS17. PRS17 exhibits a molecular mechanism whereby mutations act synergistically to alter the flap dynamics resulting in significantly weaker binding yet maintaining active site contacts with darunavir.

show abstract

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

Cited by 52 publications

References 55 publications

Discovery of HIV Type 1 Aspartic Protease Hit Compounds through Combined Computational Approaches

Discovery of HIV Type 1 Aspartic Protease Hit Compounds through Combined Computational Approaches

Binding free energy calculations on E‐selectin complexes with sLe^x oligosaccharide analogs

Structural Studies of a Rationally Selected Multi-Drug Resistant HIV-1 Protease Reveal Synergistic Effect of Distal Mutations on Flap Dynamics

Contact Info

Product

Resources

About

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

Cited by 52 publications

References 55 publications

Discovery of HIV Type 1 Aspartic Protease Hit Compounds through Combined Computational Approaches

Discovery of HIV Type 1 Aspartic Protease Hit Compounds through Combined Computational Approaches

Binding free energy calculations on E‐selectin complexes with sLex oligosaccharide analogs

Structural Studies of a Rationally Selected Multi-Drug Resistant HIV-1 Protease Reveal Synergistic Effect of Distal Mutations on Flap Dynamics

Contact Info

Product

Resources

About

Binding free energy calculations on E‐selectin complexes with sLe^x oligosaccharide analogs