Ansätze zur Beschreibung und Vorhersage der Bindungsaffinität niedermolekularer Liganden an makromolekulare Rezeptoren

Gohlke, Holger; Klebe, G.

doi:10.1002/1521-3757(20020802)114:15<2764::aid-ange2764>3.0.co;2-i

Cited by 45 publications

(9 citation statements)

References 357 publications

(516 reference statements)

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“…[11,13] These myriad effects of fluorine make a clear understanding of the affinity of fluorinated ligands for proteins difficult, even more difficult than understanding the affinity of their nonfluorinated analogues (the affinity of nonfluorinated ligands for proteins is, to begin with, not well-understood). [14,15] Not being able to rationalize why fluorination increases the affinity of ligands makes the rational design of fluorinated ligands for target proteins particularly challenging.…”

Section: Introductionmentioning

confidence: 99%

Thermodynamic Parameters for the Association of Fluorinated Benzenesulfonamides with Bovine Carbonic Anhydrase II

Krishnamurthy

Bohall

Kim

et al. 2006

Chemistry An Asian Journal

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This paper describes a calorimetric study of the association of a series of seven fluorinated benzenesulfonamide ligands (C6HnF5−nSO2NH2) with bovine carbonic anhydrase II (BCA). Quantitative structure–activity relationships between the free energy, enthalpy, and entropy of binding and pKa and log P of the ligands allowed the evaluation of the thermodynamic parameters in terms of the two independent effects of fluorination on the ligand: its electrostatic potential and its hydrophobicity. The parameters were partitioned to the three different structural interactions between the ligand and BCA: the ZnII cofactor–sulfonamide bond (≈65 % of the free energy of binding), the hydrogen bonds between the ligand and BCA (≈10 %), and the contacts between the phenyl ring of the ligand and BCA (≈25 %). Calorimetry revealed that all of the ligands studied bind in a 1:1 stoichiometry with BCA; this result was confirmed by 19F NMR spectroscopy and X‐ray crystallography (for complexes with human carbonic anhydrase II).

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Section: Introductionmentioning

confidence: 99%

Thermodynamic Parameters for the Association of Fluorinated Benzenesulfonamides with Bovine Carbonic Anhydrase II

Krishnamurthy

Bohall

Kim

et al. 2006

Chemistry An Asian Journal

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“…

The introduction of the lock-and-key principle to explain the specificity of enzyme reactions by Fischer in 1894, [1] has provided us a metaphor of molecular recognition, a fundamental mechanism utilized in almost all biological processes. [2,3] On the other hand, it is possible and of great interest to probe such recognition mechanism on the molecular level in a microscopic model system, which is amenable to high-level ab initio calculations. [2,3] On the other hand, it is possible and of great interest to probe such recognition mechanism on the molecular level in a microscopic model system, which is amenable to high-level ab initio calculations.

…”

mentioning

confidence: 99%

“…A detailed description of the underlying intermolecular interactions of enzyme-substrate templates is, however, not yet fully accessible with simplified molecular modeling approaches currently used in virtual screening and rational drug design. [2,3] On the other hand, it is possible and of great interest to probe such recognition mechanism on the molecular level in a microscopic model system, which is amenable to high-level ab initio calculations. Here, we aim at a quantitative analysis of a microscopic lock-and-key model using pulsed-jet Fourier-transform microwave (FTMW) spectroscopy and ab initio methods.…”

mentioning

confidence: 99%

Lock‐and‐Key Principle on a Microscopic Scale: The Case of the Propylene Oxide⋅⋅⋅Ethanol Complex

Borho

2007

Angewandte Chemie

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Molekulare Erkennung: Die Bindung zwischen Ethanol und Propylenoxid (PO) ähnelt dem Schlüssel‐Schloss‐Prinzip, wobei (R)‐PO das starre Schloss und die (G−)‐, (G+)‐ und T‐Konformere von EtOH die unterschiedlichen Schlüssel sind (siehe Bild; C gelb, O rot). Die Analyse von sechs wasserstoffbrückengebundenen PO⋅⋅⋅EtOH‐Konformeren mithilfe von Rotationsspektroskopie und Ab‐initio‐Rechnungen zeigt, welcher EtOH‐Schlüssel am besten in das PO‐Schloss passt.

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“…The strength and specificity of binding is governed both by the formation of selective solute-solute interactions and by solvent effects. [1][2][3][4] Although the structures and association thermochemistry of many biological complexes in solution have been determined, these data do not provide a complete description of the recognition process. [5] The challenge for researchers aiming to achieve a more complete understanding of the molecular recognition process is the separation of solvent effects from solute-solute interactions, something never-before accomplished for a biomolecular complex.…”

mentioning

confidence: 99%

Partitioning of Solvent Effects and Intrinsic Interactions in Biological Recognition

2004

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The association of molecules to form specific, noncovalent complexes is central to many biological processes. The strength and specificity of binding is governed both by the formation of selective solute-solute interactions and by solvent effects. [1][2][3][4] Although the structures and association thermochemistry of many biological complexes in solution have been determined, these data do not provide a complete description of the recognition process.[5] The challenge for researchers aiming to achieve a more complete understanding of the molecular recognition process is the separation of solvent effects from solute-solute interactions, something never-before accomplished for a biomolecular complex. Herein, we describe a novel methodology to perform this task. Our approach involves comparison of the energetic stabilities of solvated complexes with those of their desolvated (gaseous) counterparts.The enthalpy of association in solution (DH assoc ) can be expressed as the sum of the enthalpic contributions made by intrinsic solute-solute interactions (DH intrin ) and solvent effects (DH solv ), as shown in Equation (1).The DH assoc term can be determined directly by isothermal titration calorimetry (ITC) [6] or from a vant Hoff analysis of the temperature dependence of the association constant. [7] The strength of the solute-solute interactions is most reliably determined in the absence of solvent, that is, in vacuo. In principle, DH intrin can be determined from the temperature dependence of the equilibrium constant for the association of the complex in the gas phase, that is, from the slope of a vant Hoff plot. This slope corresponds to DH assoc,g , the association enthalpy of the gaseous complex. However, such measurements are generally not possible for biologically relevant molecules because of their extremely low vapor pressures. Furthermore, measurements of this kind probably would not provide the desired thermodynamic information since the structure of the complex formed in the gas phase is unlikely to resemble the structure in solution.[8] A more useful quantity is the energetic stability of the biomolecular complex formed initially in solution and then dehydrated such that it retains the essential aspects of its solution structure. Transfer of biomolecular complexes from the aqueous phase to the gas phase by electrospray or nanoelectrospray ionization readily affords the desolvated species. The value of DH assoc,g cannot be determined directly but can be estimated from the Arrhenius activation energy (E a ) for the dissociation of the desolvated complex at thermal equilibrium. The value E a is related to the enthalpy of activation for the dissociation of the complex, DH°d iss,g (E a = DH°d iss,g + RT), [9] which can provide a good approximation of the magnitude of DH assoc,g (opposite sign to that of DH°d iss,g ) if the reaction is assumed to be barrierless (that is, no reverse activation energy).[10] If the reaction is not barrierless, determination of DH°d iss,g yields an overestimation of DH assoc,g . P...

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Ansätze zur Beschreibung und Vorhersage der Bindungsaffinität niedermolekularer Liganden an makromolekulare Rezeptoren

Cited by 45 publications

References 357 publications

Thermodynamic Parameters for the Association of Fluorinated Benzenesulfonamides with Bovine Carbonic Anhydrase II

Thermodynamic Parameters for the Association of Fluorinated Benzenesulfonamides with Bovine Carbonic Anhydrase II

Lock‐and‐Key Principle on a Microscopic Scale: The Case of the Propylene Oxide⋅⋅⋅Ethanol Complex

Partitioning of Solvent Effects and Intrinsic Interactions in Biological Recognition

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