Tracing the Detail: How Mutations Affect Binding Modes and Thermodynamic Signatures of Closely Related Aldose Reductase Inhibitors

Koch, C.; Heine, A.; Klebe, G.

doi:10.1016/j.jmb.2010.11.058

Cited by 24 publications

(34 citation statements)

References 26 publications

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“…2c) also demonstrated apparent entropy-enthalpy compensation, attributed by the authors to solvent ordering effects [8]. Recent work has also found that receptor mutations can cause minimal changes in the overall free energy of binding and minimal structural changes in X-ray or NMR structures of bound ligands but extreme changes in the enthalpic and entropic contributions to binding, interpreted as suggesting large changes in the mechanism of binding [1,2,6]. …”

Section: Experimental Evidence For Compensationmentioning

confidence: 99%

“…These methods must either use a crude model of of ligand entropy with poor accuracy and convergence properties [91–93] or ignore differences in ligand binding entropies altogether and assume enthalpies alone are predictive of affinity, a point contested by both experimental [6,7] and computational [74] studies (also recently reviewed [84]).…”

Section: Ramifications For Ligand Engineeringmentioning

confidence: 99%

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Entropy-Enthalpy Compensation: Role and Ramifications in Biomolecular Ligand Recognition and Design

Chodera

Mobley

2013

Annu. Rev. Biophys.

453

440

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Recent calorimetric studies of small molecule interactions with biomolecular targets have generated renewed interest in the phenomenon of entropy-enthalpy compensation. In these studies, entropic and enthalpic contributions to binding are observed to vary substantially and in an opposing manner as the ligand or protein is modified while the binding free energy varies little. In severe examples, engineered enthalpic gains can lead to completely compensating entropic penalties, frustrating ligand design. Here, we examine the evidence for compensation, as well as its potential origins, prevalence, severity, and ramifications for ligand engineering. We find the evidence for severe compensation to be weak in light of the large magnitude of and correlation between errors in experimental measurements of entropic and enthalpic contributions to binding, though a limited form of compensation may be common. Given the difficulty of predicting or measuring entropic and enthalpic changes to useful precision, or using this information in design, we recommend ligand engineering efforts instead focus on computational and experimental methodologies to directly assess changes in binding free energy.

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Section: Experimental Evidence For Compensationmentioning

confidence: 99%

Section: Ramifications For Ligand Engineeringmentioning

confidence: 99%

Entropy-Enthalpy Compensation: Role and Ramifications in Biomolecular Ligand Recognition and Design

Chodera

Mobley

2013

Annu. Rev. Biophys.

453

440

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“…In the crystal structure of T113S/IDD383 complex, the percentages of the two corresponding configurations are 72% and 28%; and in the T113S/IDD594 complex, they are 68% and 32% (31). …”

mentioning

confidence: 99%

Electrostatic Fields near the Active Site of Human Aldose Reductase: 2. New Inhibitors and Complications Caused by Hydrogen Bonds

Cohen

Boxer

2011

Biochemistry

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Vibrational Stark effect spectroscopy was used to measure electrostatic fields in the hydrophobic region of the active site of human aldose reductase (hALR2). A new nitrile-containing inhibitor was designed and synthesized, and the x-ray structure of its complex, along with cofactor NADP+, with wild-type hALR2 was determined at 1.3 Å resolution. The nitrile is found to be in close proximity to T113, consistent with a hydrogen bond interaction. Two vibrational absorption peaks were observed at room temperature in the nitrile region when the inhibitor binds to wild-type hALR2, indicating that the nitrile probe experiences two different microenvironments, and these could be empirically separated into a hydrogen bonded and non-hydrogen bonded population by comparison with the mutant T113A, where a hydrogen bond to the nitrile is not present. Classical molecular dynamics simulations based on the structure predict a double-peaked distribution in protein electric fields projected along the nitrile probe. The interpretation of these two peaks as a hydrogen bond formation-dissociation process between the probe nitrile group and a nearby amino acid side chain is used to explain the observation of two IR bands, and the simulations were used to investigate the molecular details of this conformational change. Hydrogen bonding complicates the simplest analysis of vibrational frequency shifts as being due solely to electrostatic interactions through the vibrational Stark effect, and the consequences of this complication are discussed.

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“…Thus, both MS gas‐phase measurements and IC 50 solution studies indicate that FID is the strongest binder. This is even more the case in the published11, 12 isothermal titration calorimetry (ITC) studies, for which the ratio between the K d of 594 and of FID is 10.…”

Section: Resultsmentioning

confidence: 96%

“…On the other hand, some of them also have another moiety, which binds to the so‐called “specificity pocket,” formed by residues of the three external loops of AR adjacent to the anion binding pocket 10. In solution, FID binds AR more strongly (with the hydantoin moiety; K d : 6.5 n M 11) than 594 (with the carboxylic acid moiety; K d : 61 n M 12), as confirmed in the present study by competition experiments monitored by native MS and by IC 50 measurements. To characterize the binding in solution, we have also measured the IC 50 values (a measure of binding in the case of an enzyme).…”

Section: Introductionmentioning

confidence: 99%

Crystal packing modifies ligand binding affinity: The case of aldose reductase

et al. 2012

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The relationship between the structures of protein–ligand complexes existing in the crystal and in solution, essential in the case of fragment-based screening by X-ray crystallography (FBS-X), has been often an object of controversy. To address this question, simultaneous co-crystallization and soaking of two inhibitors with different ratios, Fidarestat (FID; Kd = 6.5 nM) and IDD594 (594; Kd = 61 nM), which bind to h-aldose reductase (AR), have been performed. The subatomic resolution of the crystal structures allows the differentiation of both inhibitors, even when the structures are almost superposed. We have determined the occupation ratio in solution by mass spectrometry (MS) Occ(FID)/Occ(594) = 2.7 and by X-ray crystallography Occ(FID)/Occ(594) = 0.6. The occupancies in the crystal and in solution differ 4.6 times, implying that ligand binding potency is influenced by crystal contacts. A structural analysis shows that the Loop A (residues 122–130), which is exposed to the solvent, is flexible in solution, and is involved in packing contacts within the crystal. Furthermore, inhibitor 594 contacts the base of Loop A, stabilizing it, while inhibitor FID does not. This is shown by the difference in B-factors of the Loop A between the AR–594 and AR–FID complexes. A stable loop diminishes the entropic energy barrier to binding, favoring 594 versus FID. Therefore, the effect of the crystal environment should be taken into consideration in the X-ray diffraction analysis of ligand binding to proteins. This conclusion highlights the need for additional methodologies in the case of FBS-X to validate this powerful screening technique, which is widely used.

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Tracing the Detail: How Mutations Affect Binding Modes and Thermodynamic Signatures of Closely Related Aldose Reductase Inhibitors

Cited by 24 publications

References 26 publications

Entropy-Enthalpy Compensation: Role and Ramifications in Biomolecular Ligand Recognition and Design

Entropy-Enthalpy Compensation: Role and Ramifications in Biomolecular Ligand Recognition and Design

Electrostatic Fields near the Active Site of Human Aldose Reductase: 2. New Inhibitors and Complications Caused by Hydrogen Bonds

Crystal packing modifies ligand binding affinity: The case of aldose reductase

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