Methyl, Ethyl, Propyl, Butyl: Futile But Not for Water, as the Correlation of Structure and Thermodynamic Signature Shows in a Congeneric Series of Thermolysin Inhibitors

Krimmer, S.G.; Betz, Michael; Heine, A.; Klebe, G.

doi:10.1002/cmdc.201400013

Cited by 74 publications

(121 citation statements)

References 94 publications

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“…Often this reflected binding of the ligands on the surface of their proteins, allowing the ligand to grow into unfilled areas of the site and solvent (35)(36)(37)(38)(39). In the case of FabI, the enzyme responds to a series of six side-chain elongations of diphenyl ethers with a smooth shift of Ile207 and 0.5-0.9 Å movements of Tyr147 and Val201 (40) (SI Appendix, Fig.…”

Section: Conformations In Other Lysozyme Cavities Recapitulate the Threementioning

confidence: 99%

Homologous ligands accommodated by discrete conformations of a buried cavity

Merski

Fischer

Balius

et al. 2015

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

114

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Conformational change in protein–ligand complexes is widely modeled, but the protein accommodation expected on binding a congeneric series of ligands has received less attention. Given their use in medicinal chemistry, there are surprisingly few substantial series of congeneric ligand complexes in the Protein Data Bank (PDB). Here we determine the structures of eight alkyl benzenes, in single-methylene increases from benzene to n-hexylbenzene, bound to an enclosed cavity in T4 lysozyme. The volume of the apo cavity suffices to accommodate benzene but, even with toluene, larger cavity conformations become observable in the electron density, and over the series two other major conformations are observed. These involve discrete changes in main-chain conformation, expanding the site; few continuous changes in the site are observed. In most structures, two discrete protein conformations are observed simultaneously, and energetic considerations suggest that these conformations are low in energy relative to the ground state. An analysis of 121 lysozyme cavity structures in the PDB finds that these three conformations dominate the previously determined structures, largely modeled in a single conformation. An investigation of the few congeneric series in the PDB suggests that discrete changes are common adaptations to a series of growing ligands. The discrete, but relatively few, conformational states observed here, and their energetic accessibility, may have implications for anticipating protein conformational change in ligand design.

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Section: Conformations In Other Lysozyme Cavities Recapitulate the Threementioning

confidence: 99%

Homologous ligands accommodated by discrete conformations of a buried cavity

Merski

Fischer

Balius

et al. 2015

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

114

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“…For example, the Klebe lab has studied water effects in thermolysin using ITC and high resolution crystal structures [5–7]. Using ligands with either a terminal methyl or a terminal carboxylate or both moieties that bind in the S2’ site, they find that the energetics are dependent on the route taken to the doubly substituted ligand [5].…”

Section: 1 Enthalpy Driven Hydrophobic Effects?mentioning

confidence: 99%

“…In this “non-classical hydrophobic effect,” a more negative enthalpy was observed when rigid water networks formed on the surface of a hydrophobic ligand in the bound complex. In other studies by this group [6, 7], a series of 12 different ligands was examined where the substituent binding to the S2’ site in thermolysin ranged from hydrogen to longer alkyl chains to a benzene moiety. While the ΔG varied from −7.52 to −9.73 kcal/mol (ΔΔG = 2.21 kcal/mol), the associated enthalpy varied from −2.50 to −8.03 kcal/mol (ΔΔH = 5.53 kcal/mol), a much larger range.…”

Section: 1 Enthalpy Driven Hydrophobic Effects?mentioning

confidence: 99%

Thermodynamics and solvent linkage of macromolecule–ligand interactions

Duff

Howell

2015

Methods

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Binding involves two steps, desolvation and association. While water is ubiquitous and occurs at high concentration, it is typically ignored. In vitro experiments typically use infinite dilution conditions, while in vivo, the concentration of water is decreased due to the presence of high concentrations of molecules in the cellular milieu. This review discusses isothermal titration calorimetry approaches that address the role of water in binding. For example, use of D2O allows the contribution of solvent reorganization to the enthalpy component to be assessed. Further, the addition of osmolytes will decrease the water activity of a solution and allow effects on Ka to be determined. In most cases, binding becomes tighter in the presence of osmolytes as the desolvation penalty associated with binding is minimized. In other cases, the osmolytes prefer to interact with the ligand or protein, and if their removal is more difficult than shedding water, then binding can be weakened. These complicating layers can be discerned by different slopes in ln(Ka) vs osmolality plots and by differential scanning calorimetry in the presence of the osmolyte.

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“…Detailed thermodynamic and structural analyses of the water network and its perturbation by ligands can distinguish water molecules whose repulsion from the binding site is favorable or unfavorable in terms of their contribution to binding free energy and its components [22,23,24,25,26]. Although an assignment of free-energy and its components to water molecules is an approximation it contributes to our understanding of the role of water in ligand binding.…”

Section:  Size-dependence Of Ligand-protein Interactionsmentioning

confidence: 99%

The Impact of Binding Thermodynamics on Medicinal Chemistry Optimizations

Ferenczy

Keserü

2015

Future Med. Chem.

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Background: Ligand binding thermodynamics has been attracted considerable interest in the past decade owing to the recognized relation between binding thermodynamic profile and the physicochemical and druglike properties of compounds. Discussion: • Affinity improvements in drug discovery optimizations can be either enthalpically or entropically driven. In this review the relation between optimization strategies and ligand properties are presented based on the structural and thermodynamic analysis of ligand-protein complex formation. Conclusions: The control of the binding thermodynamic profile is beneficial for the balanced affinity and physicochemical properties of drug candidates and early phase optimization gives more opportunity to this control.

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Methyl, Ethyl, Propyl, Butyl: Futile But Not for Water, as the Correlation of Structure and Thermodynamic Signature Shows in a Congeneric Series of Thermolysin Inhibitors

Cited by 74 publications

References 94 publications

Homologous ligands accommodated by discrete conformations of a buried cavity

Homologous ligands accommodated by discrete conformations of a buried cavity

Thermodynamics and solvent linkage of macromolecule–ligand interactions

The Impact of Binding Thermodynamics on Medicinal Chemistry Optimizations

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