Enthalpy-entropy compensation in drug-receptor binding

Gilli, Paola; Ferretti, Valeria; Gilli, Gastone; Borea, Pier Andrea

doi:10.1021/j100056a024

Cited by 223 publications

(188 citation statements)

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“…The information provided by these data could be useful from a pharmacological point of view to discover new thermodynamic relationships related to drug-receptor interactions and their molecular mechanisms [27].…”

Section: Discussionmentioning

confidence: 99%

“…All buffer solutions were adjusted to maintain a constant pH of 7.4 at the desired temperature. in solution but appears to be typical as far as membrane receptor binding is concerned [27]. 2) Cp° is not equal to zero [9,28].…”

Section: Saturation and Competition Binding Experimentsmentioning

confidence: 99%

“…All buffer solutions were adjusted to maintain a constant pH of 7.4 at the desired temperature. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 in solution but appears to be typical as far as membrane receptor binding is concerned [27]. 2) Cp° is not equal to zero [9,28].…”

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confidence: 99%

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Binding thermodynamics at the human cannabinoid CB1 and CB2 receptors

Merighi

Simioni²,

Gessi³

et al. 2010

Biochemical Pharmacology

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The thermodynamic parameters G°, H° and S° of the binding equilibrium of agonists and antagonists at cannabinoid CB 1 and CB 2 receptors were determined by means of affinity measurements at different temperatures and van't Hoff plots were constructed. Affinity constants were measured on CHO cells transfected with the human CB 1 antagonists. Collectively, these data show that agonist binding is always totally entropy-driven while antagonist binding is enthalpy and entropy-driven, indicating that CB 1 and CB 2 receptors are thermodynamically discriminated. These data could give new details on the nature of the forces driving the CB 1 and CB 2 binding at a molecular level. Enthalpy, entropy, free energy and binding affinity for each ligand to its receptor can all be assessed and therefore the optimal binding profile discovered. Carrying out these binding investigations as early as possible in the discovery process increases the probability that a lead compound will become a successful pharmaceutical compound.Keywords: Binding mechanisms; Binding thermodynamics; drug development; enthalpy-entropy compensation; Pharmacokinetics. Page 4 of 27A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 4 INTRODUCTIONThe thermodynamic analysis of the binding equilibrium of a drug to its receptor allows us to evaluate the two components, standard enthalpy ( H°) and standard entropy ( S°), of the standard free energy ( G°) of the binding equilibrium [1]. It is often assumed that H° and S° terms represent the two classes of factors responsible for the drug-receptor recognition phenomenon: nonbonded interactions, as hydrogen bonding and multipolar or dispersive interactions (which are mainly to be related to the enthalpic term), and solvent reorganization (which is most properly associated with the entropic one) [2]. There are two main strategies for the evaluation of G°, H° A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 Milano, Italy). All other reagents were purchased from Sigma-Aldrich (Milano, Italy). Cell Culture.hCHO-CB 1 and hCHO-CB 2 were grown adherently and mantained in Ham's Medium with nutrient mixture F12 (Ham's/F12), containing 10% fetal calf serum, penicillin (100 U/ml), streptomycin (100 g/ml), L-glutamine (2 mM) and Geneticin (G418, 0,4 mg/ml) at 37°C in 5% CO 2 /95% air.Cells were split 2 or 3 times weekly at a ratio between 1:5 and 1:20. Membrane Preparation.For membrane preparation the culture medium was removed. The cells were washed with PBS and scraped off T75 flasks in ice-cold hypotonic buffer (5 mM Tris HCl, 2 mM EDTA, pH 7.4). The ce...

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Section: Discussionmentioning

confidence: 99%

Section: Saturation and Competition Binding Experimentsmentioning

confidence: 99%

mentioning

confidence: 99%

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Binding thermodynamics at the human cannabinoid CB1 and CB2 receptors

Merighi

Simioni²,

Gessi³

et al. 2010

Biochemical Pharmacology

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“…The observation that increasing the enthalpy of the pK a -dependent structural, component interactions (Zn II À N bond and hydrogen-bond network; Scheme 1) lowers the entropy of these interactions is compatible with the phenomenon of enthalpy/entropy compensation. [38,39] In the physical model for enthalpy/entropy compensation, more-exothermic binding occurs with a less-favorable entropy than less-exothermic binding because of the lower mobility at the protein-ligand interface for the moreexothermic binding event. [38] Equation (8) shows that increasing the hydrophobicity (i.e., log P) of the benzenesulfonamide ligand decreases ÀTDS ArSO 2 NH À .…”

Section: A C H T U N G T R E N N U N G [Eq a C H T U N G T R E N N Umentioning

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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“…The temperature dependence of the ligand-GAL activation affinities were used to explore the evidence for entropy-enthalpy compensation, [41][42][43] characteristic of hydrophobic interactions in aqueous ligand-protein systems. [44][45][46][47][48] …”

Section: Introductionmentioning

confidence: 99%

Designing allosteric peptide ligands targeting a globular protein

et al. 2006

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Patented signal analytic algorithms applied to hydrophobically transformed, numerical amino acid sequences have previously been used to design short, protein‐targeted, L or D retro‐inverso peptides. These peptides have demonstrated allosteric and/or indirect agonist effects on a variety of G‐protein and tyrosine kinase coupled membrane receptors with 30% to over 80% hit rates. Here we extend these approaches to a globular protein target. We designed eight peptide ligands targeting an ELISA antibody responsive protein, β‐galactosidase, βGAL. Three of the eight 14mer peptides allosterically activated βGAL with ELISA methodology. Using Bayesian statistics, this 38% hit rate would have occurred 2 × 10−9 by chance. These peptides demonstrated binding site competitive or noncompetitive interactions, suggesting allosteric site multiplicity with respect to their βGAL binding‐mediated ELISA signal. Kinetic studies demonstrated the temperature dependence of the βGAL peptide binding functions. Using the van't Hoff relation, we found evidence for enthalpy–entropy compensation. This relation is often found for hydrophobic interactions in aqueous media, and is consistent with the postulated hydrophobic series encoding underlying our protein‐targeted, peptide design methods. It appears that our algorithmic, hydrophobic autocovariance eigenvector template approach to the design of allosteric peptides targeting membrane receptors may also be applicable to the design of peptide ligands targeting nonmembrane involved globular proteins. © 2006 Wiley Periodicals, Inc. Biopolymers 85: 38–59, 2007.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

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Enthalpy-entropy compensation in drug-receptor binding

Cited by 223 publications

References 1 publication

Binding thermodynamics at the human cannabinoid CB1 and CB2 receptors

Binding thermodynamics at the human cannabinoid CB1 and CB2 receptors

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

Designing allosteric peptide ligands targeting a globular protein

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