Rapid Screening of Binding Constants by Calibrated Competitive <sup>1</sup>H NMR Spectroscopy

Heath, Richard E.; Dykes, Graham M.; Fish, Heather; Smith, David K.

doi:10.1002/chem.200390094

Cited by 38 publications

(25 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…16 It has been shown that phenolic groups on calixarenes can interact with anions, 17 and phenolic compounds have also been employed as anion sensors. 18 We recently used a high-throughput assay 19 to screen the ability of a number of simple bisamides and phenols to bind chloride anions in acetonitrile solution. This assay identified catechol as a potentially useful chloride anion binding fragment.…”

Section: Introductionmentioning

confidence: 99%

Anion binding by catechols—an NMR, optical and electrochemical study

2006

Self Cite

View full text Add to dashboard Cite

The X-ray structure of the ClC chloride channel made it clear that O-H...chloride interactions play a key role in important biological membrane-bound systems, however, surprisingly this type of interaction has only been rarely exploited for the development of synthetic anion receptors. This paper therefore reports the anion binding strengths and selectivities of some simple commercially available bis-phenols. In particular, we compare catechol (1,2-dihydroxybenzene) and resorcinol (1,3-dihydroxybenzene) which show interesting and different selectivities between the halide anions in acetonitrile solution. Catechol binds tetrabutylammononium (TBA) chloride almost 30 times more strongly than TBA bromide, whilst for resorcinol, this difference drops to a factor of ca. 3.5. It is suggested that this is a consequence of the bite angle of the chelating hydrogen bonding groups of catechol being particularly appropriate for effective binding of the smaller anion. The oxidation of catechol to ortho-quinone is perturbed by the addition of chloride anions, as probed via cyclic voltammetry, and this compound can therefore be considered to act as an electrochemical sensor for chloride. Nitrocatechol is able to bind chloride anions more strongly than catechol as a consequence of its enhanced acidity and hence greater hydrogen bond donor character. Furthermore, nitrocatechol senses the bound anion via changes in its UV-visible spectrum. Notably, binding still occurs even in the presence of small amounts of competitive solvents (e.g. water). This observation has biomimetic importance as wet acetonitrile has some similarity in terms of overall polarity and hydrogen bond competition to the solvent shielded interiors of biological macromolecules and membranes--such as the environment within the ClC chloride channel itself. Finally, we report that catechol undergoes a unique colorimetric response on the addition of basic anions, such as fluoride. We can assign this response as being due to oxidative degradation of catechol catalysed by the basic anions (which bind to, and deprotonate, the catechol). This process is somewhat analogous to the well-known metal catalysed oxidation of catechol which can take place in aqueous solution. The speed of response and easily monitored and distinctive colour change induced by fluoride anions indicates this may be a useful mechanism for exploitation in the development of selective fluoride sensors.

show abstract

Section: Introductionmentioning

confidence: 99%

Anion binding by catechols—an NMR, optical and electrochemical study

2006

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recently,w ed emonstrated that dissolution dynamic nuclear polarization (d-DNP), ah yperpolarization technique to increase the NMR sensitivity by several orders of magnitude, [5] is applicable to 19 FNMR in screening experiments. [6] Al imitation of 19 FNMR detection lies in the omission of non-fluorinated drug candidates.H owever, if as uitable fluorinated ligand is known for ap rotein of interest, this ligand can be used in competitive binding experiments to report on other, nonfluorinated ligands.C ompetitive binding experiments have been demonstrated using proton-or fluorine-based NMR spectroscopy, [7][8][9][10] as well as with hyperpolarized long-lived spin states. [11] If the reporter ligand is in fast exchange with the protein, ligands with arange of binding affinities can thus be identified, such as using the "fluorine chemical shift aniso-tropy and exchange for screening" method.…”

mentioning

confidence: 99%

Affinity Screening Using Competitive Binding with Fluorine‐19 Hyperpolarized Ligands

Kim

Hilty

2015

Angew Chem Int Ed

View full text Add to dashboard Cite

Fluorine-19 NMR and hyperpolarization form a powerful combination for drug screening. Under a competitive equilibrium with a selected fluorinated reporter ligand, the dissociation constant (KD) of other ligands of interest is measurable using a single-scan Carr-Purcell-Meiboom-Gill (CPMG) experiment, without the need for a titration. This method is demonstrated by characterizing the binding of three ligands with different affinities for the serine protease trypsin. Monte Carlo simulations show that the highest accuracy is obtained when about one-half of the bound reporter ligand is displaced in the binding competition. Such conditions can be achieved over a wide range of affinities, allowing for rapid screening of non-fluorinated compounds when a single fluorinated ligand to the binding pocket of interest is known.

show abstract

“…host-guest complexes such as those considered in this study. Generally, the widely applied analytical tools for studying competitive phenomena of non-covalent binding are electrospray ionization mass spectrometry (ESI-MS), [18][19][20][21][22][23][24] for measurements in the gas phase, and NMR techniques, [25][26][27] in solution. However, practical applications of supramolecular receptors, such as chromatographic applications or sensing devices, are applied at the gas-solid or liquid-solid interface.…”

Section: Introductionmentioning

confidence: 99%

Selectivity assessment in host–guest complexes from single-crystal X-ray diffraction data: the cavitand–alcohol case

et al. 2014

View full text Add to dashboard Cite

The determination of selectivity is central to the development of molecular receptors. Competition binding experiments based on the relative binding ratios are commonly used to evaluate relative binding constants. When more than one species binds to the same active site of a receptor, the crystallographic evaluation of the occupancy factors of each ligand could be very informative about their relative affinity. However, in the presence of overlapped electron densities, the statistical occupancy factors are hard to retrieve using conventional crystal structure refinement. Here, we present an original method to evaluate the relative binding constants based on the direct treatment of the diffraction intensities obtained from isomorphous single crystals grown in the presence of binary mixtures of competitive ligands. This method was developed and first applied to evaluate the affinity of a tetraphosphonate cavitand receptor towards short-chain alcohols. In the easier cases, wherein the electron densities of the two alcohols are less overlapped, the occupancy factors for guest molecules obtained in conventional structural refinement are in good agreement with the values calculated from the direct comparison of diffraction intensities. The affinity constants were estimated from the calculated occupancy factors, considering the molar ratios of alcohols used in the competition experiments. The congruence of the method has been tested on several binary mixtures using different concentration ratios of alcoholic guests. In general, for a given alcoholic pair, the different molar ratios of alcohols, used in the crystallization batch, produce a trend of the occupancy factors in agreement with the binding constant ratios of the two alcohols. From 32 data sets collected at the Elettra synchrotron for six short alkylic chain guest molecules, we evaluated the binding constant ratios with a good internal consistency. The relative binding constants for these six alcohols were evaluated from the entire statistical sample (EtOH, 8.8 > 1-PrOH, 2.2 > MeOH, 1.3 > 2-PrOH, 1.00 > 2-BuOH, 0.32 > 1-BuOH, 0.11, using 2-PrOH as reference with an arbitrary value of 1) and are in good agreement with the structural parameters of host–guest interactions observed in the corresponding crystal structures. In particular, the binding constant decreases with the increase in the host–guest H-bond distance, which follows the increase in the length of the alkyl chain of the alcoholic guest. Moreover, quartz crystal microbalance (QCM) measurements and fluorescence data have been compared and discussed with respect to the relative affinity scale obtained by crystallography

show abstract

Rapid Screening of Binding Constants by Calibrated Competitive ¹H NMR Spectroscopy

Cited by 38 publications

References 46 publications

Anion binding by catechols—an NMR, optical and electrochemical study

Anion binding by catechols—an NMR, optical and electrochemical study

Affinity Screening Using Competitive Binding with Fluorine‐19 Hyperpolarized Ligands

Selectivity assessment in host–guest complexes from single-crystal X-ray diffraction data: the cavitand–alcohol case

Contact Info

Product

Resources

About

Rapid Screening of Binding Constants by Calibrated Competitive 1H NMR Spectroscopy

Cited by 38 publications

References 46 publications

Anion binding by catechols—an NMR, optical and electrochemical study

Anion binding by catechols—an NMR, optical and electrochemical study

Affinity Screening Using Competitive Binding with Fluorine‐19 Hyperpolarized Ligands

Selectivity assessment in host–guest complexes from single-crystal X-ray diffraction data: the cavitand–alcohol case

Contact Info

Product

Resources

About

Rapid Screening of Binding Constants by Calibrated Competitive ¹H NMR Spectroscopy