Thermodynamic rules for the design of high affinity HIV-1 protease inhibitors with adaptability to mutations and high selectivity towards unwanted targets

Ohtaka, Hiroyasu

doi:10.1016/j.biocel.2004.02.021

Cited by 70 publications

(59 citation statements)

References 39 publications

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“…This analysis is consistent with NMR relaxation data and is very reasonable given the high glycine content of the flap tips. As was shown by calorimetric experiments, a large favorable entropy change is also the major driving force for high binding affinity of current HIV-1 PR inhibitors [46,47]. However, in this case it is the favorable solvation entropy associated with the burial of a large hydrophobic surface upon inhibitor binding.…”

Section: Proposed Molecular Mechanisms Of Resistancementioning

confidence: 96%

Targeting structural flexibility in HIV-1 protease inhibitor binding

Horn̆ák

Simmerling

2007

Drug Discovery Today

108

104

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SummaryHIV-1 protease remains an important AIDS drug target. Even though it has been known that ligand binding induces large conformational changes in the protease, the dynamic aspects of binding have been largely ignored. Several computational models describing protease dynamics have been reported recently. These have reproduced experimental observations, and also explained how ligands gain access to the binding site through dynamic behavior of the protease. Specifically, the transitions between three different conformations of the protein have been modeled in atomic detail. Two of these forms were determined by crystallography, the third one was implied by NMR experiments. Based on these computational models, it has been suggested that binding of inhibitors in allosteric sites may affect protease flexibility and disrupt its function.

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Section: Proposed Molecular Mechanisms Of Resistancementioning

confidence: 96%

Targeting structural flexibility in HIV-1 protease inhibitor binding

Horn̆ák

Simmerling

2007

Drug Discovery Today

108

104

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“…Moreover, information on changes in entropy and enthalpy can usefully guide the design of improved drug molecules (1), with advantageous specificity (2) and physical properties (3). However, calorimetric studies of biomolecular binding and folding often reveal unexpected changes in entropy and enthalpy that are difficult to interpret in terms of physical driving forces (4)(5)(6)(7)(8).…”

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confidence: 99%

Entropy–enthalpy transduction caused by conformational shifts can obscure the forces driving protein–ligand binding

Fenley

Muddana

Gilson

2012

Proc. Natl. Acad. Sci. U.S.A.

116

150

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Molecular dynamics simulations of unprecedented duration now can provide new insights into biomolecular mechanisms. Analysis of a 1-ms molecular dynamics simulation of the small protein bovine pancreatic trypsin inhibitor reveals that its main conformations have different thermodynamic profiles and that perturbation of a single geometric variable, such as a torsion angle or interresidue distance, can select for occupancy of one or another conformational state. These results establish the basis for a mechanism that we term entropy-enthalpy transduction (EET), in which the thermodynamic character of a local perturbation, such as enthalpic binding of a small molecule, is camouflaged by the thermodynamics of a global conformational change induced by the perturbation, such as a switch into a high-entropy conformational state. It is noted that EET could occur in many systems, making measured entropies and enthalpies of folding and binding unreliable indicators of actual thermodynamic driving forces. The same mechanism might also account for the high experimental variance of measured enthalpies and entropies relative to free energies in some calorimetric studies. Finally, EET may be the physical mechanism underlying many cases of entropy-enthalpy compensation.T he entropic and enthalpic components of free energy can be informative regarding the mechanisms of biophysical processes, like protein folding and protein-ligand binding. Moreover, information on changes in entropy and enthalpy can usefully guide the design of improved drug molecules (1), with advantageous specificity (2) and physical properties (3). However, calorimetric studies of biomolecular binding and folding often reveal unexpected changes in entropy and enthalpy that are difficult to interpret in terms of physical driving forces (4-8). Some of these puzzling results are instances of entropy-enthalpy compensation (9), a common but not universal (10, 11) phenomenon in which perturbations of a system that increase the enthalpy also increase the entropy or vice versa; therefore, the net change in the free energy remains small. Experimental error in measured enthalpies, particularly when obtained by the relatively imprecise van 't Hoff method, can generate spurious entropy-enthalpy compensation (12); the nonphysical operation of Berkson's paradox (selection bias) (13) can also generate this compensation. However, analysis of collected calorimetric data for protein-ligand binding indicates that entropy-enthalpy compensation is a genuine and common physical phenomenon (13).Today, novel computational technologies, such as graphical processor units (14-17) and the specialized Anton computer (18), are enabling dramatically longer molecular dynamics (MD) simulations than hitherto feasible. The enormous conformational sampling power of these technologies has the potential to open a new window on the molecular mechanisms underlying the thermodynamics of biomolecular systems. For example, it can provide increasingly accurate estimates of thermodynamic quantities that ...

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“…In the case of HIV protease inhibitors it was shown that more enthalpic compounds possess higher adaptability to drug-resistant mutants along with more enhanced selectivity to the off target cathepsin D [27,28]. Interestingly, no correlation was observed between adaptability and binding affinity, however a reproducible correlation was found between the logarithm of the corresponding K d ratio and the proportion of binding enthalpy contribution to the binding affinity in the wild-type protease [27].…”

Section: Thermodynamic Profile Of Marketed Drugsmentioning

confidence: 99%