Binding selectivity

Last updated

In chemistry, binding selectivity is defined with respect to the binding of ligands to a substrate forming a complex. Binding selectivity describes how a ligand may bind more preferentially to one receptor than another. A selectivity coefficient is the equilibrium constant for the reaction of displacement by one ligand of another ligand in a complex with the substrate. Binding selectivity is of major importance in biochemistry [1] and in chemical separation processes.

Contents

Selectivity coefficient

The concept of selectivity is used to quantify the extent to which one chemical substance, A, binds each of two other chemical substances, B and C. The simplest case is where the complexes formed have 1:1 stoichiometry. Then, the two interactions may be characterized by equilibrium constants KAB and KAC. [note 1]

where [X] represents the concentration of substance X (A, B, C, …).

A selectivity coefficient is defined as the ratio of the two equilibrium constants.

This selectivity coefficient is in fact the equilibrium constant for the displacement reaction

It is easy to show that the same definition applies to complexes of a different stoichiometry, ApBq and ApCq. The greater the selectivity coefficient, the more the ligand C will displace the ligand B from the complex formed with the substrate A. An alternative interpretation is that the greater the selectivity coefficient, the lower the concentration of C that is needed to displace B from AB. Selectivity coefficients are determined experimentally by measuring the two equilibrium constants, KAB and KAC.

Applications

Biochemistry

In biochemistry the substrate is known as a receptor. A receptor is a protein molecule, embedded in either the plasma membrane or the cytoplasm of a cell, to which one or more specific kinds of signalling molecules may bind. A ligand may be a peptide or another small molecule, such as a neurotransmitter, a hormone, a pharmaceutical drug, or a toxin. The specificity of a receptor is determined by its spatial geometry and the way it binds to the ligand through non-covalent interactions, such as hydrogen bonding or Van der Waals forces. [2]

If a receptor can be isolated a synthetic drug can be developed either to stimulate the receptor, an agonist or to block it, an antagonist. The stomach ulcer drug cimetidine was developed as an H2 antagonist by chemically engineering the molecule for maximum specificity to an isolated tissue containing the receptor. The further use of quantitative structure-activity relationships (QSAR) led to the development of other agents such as ranitidine.

It is important to note that "selectivity" when referring to a drug is relative and not absolute. For example, in a higher dose, a specific drug molecule may also bind to other receptors than those said to be "selective".

Chelation therapy

Deferiprone.svg
Deferiprone
Penicillamine structure.png
Penicillamine

Chelation therapy is a form of medical treatment in which a chelating ligand [note 2] is used to selectively remove a metal from the body. When the metal exists as a divalent ion, such as with lead, Pb2+ or mercury, Hg2+ selectivity against calcium, Ca2+ and magnesium, Mg2+, is essential in order that the treatment does not remove essential metals. [3]

Selectivity is determined by various factors. In the case of iron overload, which may occur in individuals with β-thalessemia who have received blood transfusions, the target metal ion is in the +3 oxidation state and so forms stronger complexes than the divalent ions. It also forms stronger complexes with oxygen-donor ligands than with nitrogen-donor ligands. deferoxamine, a naturally occurring siderophore produced by the actinobacter Streptomyces pilosus and was used initially as a chelation therapy agent. Synthetic siderophores such as deferiprone and deferasirox have been developed, using the known structure of deferoxamine as a starting point. [4] [5] Chelation occurs with the two oxygen atoms.

Wilson's disease is caused by a defect in copper metabolism which results in accumulation of copper metal in various organs of the body. The target ion in this case is divalent, Cu2+. This ion is classified as borderline in the scheme of Ahrland, Chatt and Davies. [6] This means that it forms roughly equally strong complexes with ligands whose donor atoms are N, O or F as with ligands whose donor atoms are P, S or Cl. Penicillamine, which contains nitrogen and sulphur donor atoms, is used as this type of ligand binds more strongly to copper ions than to calcium and magnesium ions.

Treatment of poisoning by heavy metals such as lead and mercury is more problematical, because the ligands used do not have high specificity relative to calcium. For example, EDTA may be administered as a calcium salt to reduce the removal of calcium from bone together with the heavy metal. Factors determining selectivity for lead against zinc, cadmium and calcium have been reviewed, [7]

Chromatography

In column chromatography a mixture of substances is dissolved in a mobile phase and passed over a stationary phase in a column. A selectivity factor is defined as the ratio of distribution coefficients, which describe the equilibrium distribution of an analyte between the stationary phase and the mobile phase. The selectivity factor is equal to the selectivity coefficient with the added assumption that the activity of the stationary phase, the substrate in this case, is equal to 1, the standard assumption for a pure phase. [8] The resolution of a chromatographic column, RS is related to the selectivity factor by:

where α is selectivity factor, N is the number of theoretical plates kA and kB are the retention factors of the two analytes. Retention factors are proportional to distribution coefficients. In practice substances with a selectivity factor very close to 1 can be separated. This is particularly true in gas-liquid chromatography where column lengths up to 60 m are possible, providing a very large number of theoretical plates.

In ion-exchange chromatography the selectivity coefficient is defined in a slightly different way [9]

Solvent extraction

Solvent extraction [10] is used to extract individual lanthanoid elements from the mixtures found in nature in ores such as monazite. In one process, the metal ions in aqueous solution are made to form complexes with tributylphosphate (TBP), which are extracted into an organic solvent such as kerosene. Complete separation is effected by using a countercurrent exchange method. A number of cells are arranged as a cascade. After equilibration, the aqueous component of each cell is transferred to the previous cell and the organic component is transferred to the next cell, which initially contains only water. In this way the metal ion with the most stable complex passes down the cascade in the organic phase and the metal with the least stable complex passes up the cascade in the aqueous phase. [11]

If solubility in the organic phase is not an issue, a selectivity coefficient is equal to the ratio of the stability constants of the TBP complexes of two metal ions. For lanthanoid elements which are adjacent in the periodic table this ratio is not much greater than 1, so many cells are needed in the cascade.

Chemical sensors

Types of Chemosensors. (1.) Indicator-spacer-receptor (ISR) (2.) Indicator-Displacement Assay (IDA) Sensing.png
Types of Chemosensors. (1.) Indicator-spacer-receptor (ISR) (2.) Indicator-Displacement Assay (IDA)

A potentiometric selectivity coefficient defines the ability of an ion-selective electrode to distinguish one particular ion from others. The selectivity coefficient, KB,C is evaluated by means of the emf response of the ion-selective electrode in mixed solutions of the primary ion, B, and interfering ion, C (fixed interference method) or less desirably, in separate solutions of B and C (separate solution method). [12] For example, a potassium ion-selective membrane electrode utilizes the naturally occurring macrocyclic antibiotic valinomycin. In this case the cavity in the macrocyclic ring is just the right size to encapsulate the potassium ion, but too large to bind the sodium ion, the most likely interference, strongly.

Chemical sensors, [13] [14] are being developed for specific target molecules and ions in which the target (guest) form a complex with a sensor (host). The sensor is designed to be an excellent match in terms of the size and shape of the target in order to provide for the maximum binding selectivity. An indicator is associated with the sensor which undergoes a change when the target forms a complex with the sensor . The indicator change is usually a colour change (gray to yellow in the illustration) seen in absorbance or, with greater sensitivity, luminescence. The indicator may be attached to the sensor via a spacer, in the ISR arrangement, or it may be displaced from the sensor, IDA arrangement.

See also

Notes

  1. ↑ The constant used here are association constants. Dissociation constants are used in some contexts. A dissociation constant is the reciprocal of an association constant.
  2. ↑ The term "ligand" here refers to binding to a metal. In the definition of selectivity coefficient this "ligand" is in fact the substrate and ligand in that definition is the metal ion.

Related Research Articles

In a chemical reaction, chemical equilibrium is the state in which both the reactants and products are present in concentrations which have no further tendency to change with time, so that there is no observable change in the properties of the system. This state results when the forward reaction proceeds at the same rate as the reverse reaction. The reaction rates of the forward and backward reactions are generally not zero, but they are equal. Thus, there are no net changes in the concentrations of the reactants and products. Such a state is known as dynamic equilibrium.

In chemistry, biochemistry, and pharmacology, a dissociation constant is a specific type of equilibrium constant that measures the propensity of a larger object to separate (dissociate) reversibly into smaller components, as when a complex falls apart into its component molecules, or when a salt splits up into its component ions. The dissociation constant is the inverse of the association constant. In the special case of salts, the dissociation constant can also be called an ionization constant. For a general reaction:

In chemistry, an acid dissociation constant is a quantitative measure of the strength of an acid in solution. It is the equilibrium constant for a chemical reaction

Solubility equilibrium is a type of dynamic equilibrium that exists when a chemical compound in the solid state is in chemical equilibrium with a solution of that compound. The solid may dissolve unchanged, with dissociation, or with chemical reaction with another constituent of the solution, such as acid or alkali. Each solubility equilibrium is characterized by a temperature-dependent solubility product which functions like an equilibrium constant. Solubility equilibria are important in pharmaceutical, environmental and many other scenarios.

Cooperative binding occurs in molecular binding systems containing more than one type, or species, of molecule and in which one of the partners is not mono-valent and can bind more than one molecule of the other species. In general, molecular binding is an interaction between molecules that results in a stable physical association between those molecules.

Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate ligand and a single central metal atom. These ligands are called chelants, chelators, chelating agents, or sequestering agents. They are usually organic compounds, but this is not a necessity, as in the case of zinc and its use as a maintenance therapy to prevent the absorption of copper in people with Wilson's disease.

<span class="mw-page-title-main">Receptor (biochemistry)</span> Protein molecule receiving signals for a cell

In biochemistry and pharmacology, receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems. These signals are typically chemical messengers which bind to a receptor and produce physiological responses such as change in the electrical activity of a cell. For example, GABA, an inhibitory neurotransmitter inhibits electrical activity of neurons by binding to GABAA receptors. There are three main ways the action of the receptor can be classified: relay of signal, amplification, or integration. Relaying sends the signal onward, amplification increases the effect of a single ligand, and integration allows the signal to be incorporated into another biochemical pathway.

<span class="mw-page-title-main">Drug design</span> Inventive process of finding new medications based on the knowledge of a biological target

Drug design, often referred to as rational drug design or simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic small molecule that activates or inhibits the function of a biomolecule such as a protein, which in turn results in a therapeutic benefit to the patient. In the most basic sense, drug design involves the design of molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it. Drug design frequently but not necessarily relies on computer modeling techniques. This type of modeling is sometimes referred to as computer-aided drug design. Finally, drug design that relies on the knowledge of the three-dimensional structure of the biomolecular target is known as structure-based drug design. In addition to small molecules, biopharmaceuticals including peptides and especially therapeutic antibodies are an increasingly important class of drugs and computational methods for improving the affinity, selectivity, and stability of these protein-based therapeutics have also been developed.

The equilibrium constant of a chemical reaction is the value of its reaction quotient at chemical equilibrium, a state approached by a dynamic chemical system after sufficient time has elapsed at which its composition has no measurable tendency towards further change. For a given set of reaction conditions, the equilibrium constant is independent of the initial analytical concentrations of the reactant and product species in the mixture. Thus, given the initial composition of a system, known equilibrium constant values can be used to determine the composition of the system at equilibrium. However, reaction parameters like temperature, solvent, and ionic strength may all influence the value of the equilibrium constant.

<span class="mw-page-title-main">Dissociation (chemistry)</span> Separation of molecules or ionic compounds into smaller constituent entities

Dissociation in chemistry is a general process in which molecules (or ionic compounds such as salts, or complexes) separate or split into other things such as atoms, ions, or radicals, usually in a reversible manner. For instance, when an acid dissolves in water, a covalent bond between an electronegative atom and a hydrogen atom is broken by heterolytic fission, which gives a proton (H+) and a negative ion. Dissociation is the opposite of association or recombination.

<span class="mw-page-title-main">Host–guest chemistry</span> Supramolecular structures held together other than by covalent bonds

In supramolecular chemistry, host–guest chemistry describes complexes that are composed of two or more molecules or ions that are held together in unique structural relationships by forces other than those of full covalent bonds. Host–guest chemistry encompasses the idea of molecular recognition and interactions through non-covalent bonding. Non-covalent bonding is critical in maintaining the 3D structure of large molecules, such as proteins and is involved in many biological processes in which large molecules bind specifically but transiently to one another.

<span class="mw-page-title-main">Hill equation (biochemistry)</span> Diagram showing the proportion of a receptor bound to a ligand

In biochemistry and pharmacology, the Hill equation refers to two closely related equations that reflect the binding of ligands to macromolecules, as a function of the ligand concentration. A ligand is "a substance that forms a complex with a biomolecule to serve a biological purpose", and a macromolecule is a very large molecule, such as a protein, with a complex structure of components. Protein-ligand binding typically changes the structure of the target protein, thereby changing its function in a cell.

<span class="mw-page-title-main">Ligand (biochemistry)</span> Substance that forms a complex with a biomolecule

In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from Latin ligare, which means 'to bind'. In protein-ligand binding, the ligand is usually a molecule which produces a signal by binding to a site on a target protein. The binding typically results in a change of conformational isomerism (conformation) of the target protein. In DNA-ligand binding studies, the ligand can be a small molecule, ion, or protein which binds to the DNA double helix. The relationship between ligand and binding partner is a function of charge, hydrophobicity, and molecular structure.

The binding constant, or affinity constant/association constant, is a special case of the equilibrium constant K, and is the inverse of the dissociation constant. It is associated with the binding and unbinding reaction of receptor (R) and ligand (L) molecules, which is formalized as:

<span class="mw-page-title-main">Molecular sensor</span>

A molecular sensor or chemosensor is a molecular structure that is used for sensing of an analyte to produce a detectable change or a signal. The action of a chemosensor, relies on an interaction occurring at the molecular level, usually involves the continuous monitoring of the activity of a chemical species in a given matrix such as solution, air, blood, tissue, waste effluents, drinking water, etc. The application of chemosensors is referred to as chemosensing, which is a form of molecular recognition. All chemosensors are designed to contain a signalling moiety and a recognition moiety, that is connected either directly to each other or through a some kind of connector or a spacer. The signalling is often optically based electromagnetic radiation, giving rise to changes in either the ultraviolet and visible absorption or the emission properties of the sensors. Chemosensors may also be electrochemically based. Small molecule sensors are related to chemosensors. These are traditionally, however, considered as being structurally simple molecules and reflect the need to form chelating molecules for complexing ions in analytical chemistry. Chemosensors are synthetic analogues of biosensors, the difference being that biosensors incorporate biological receptors such as antibodies, aptamers or large biopolymers.

Equilibrium constants are determined in order to quantify chemical equilibria. When an equilibrium constant K is expressed as a concentration quotient,

Molecular binding is an attractive interaction between two molecules that results in a stable association in which the molecules are in close proximity to each other. It is formed when atoms or molecules bind together by sharing of electrons. It often, but not always, involves some chemical bonding.

In coordination chemistry, a stability constant is an equilibrium constant for the formation of a complex in solution. It is a measure of the strength of the interaction between the reagents that come together to form the complex. There are two main kinds of complex: compounds formed by the interaction of a metal ion with a ligand and supramolecular complexes, such as host–guest complexes and complexes of anions. The stability constant(s) provide(s) the information required to calculate the concentration(s) of the complex(es) in solution. There are many areas of application in chemistry, biology and medicine.

Equilibrium chemistry is concerned with systems in chemical equilibrium. The unifying principle is that the free energy of a system at equilibrium is the minimum possible, so that the slope of the free energy with respect to the reaction coordinate is zero. This principle, applied to mixtures at equilibrium provides a definition of an equilibrium constant. Applications include acid–base, host–guest, metal–complex, solubility, partition, chromatography and redox equilibria.

A ligand binding assay (LBA) is an assay, or an analytic procedure, which relies on the binding of ligand molecules to receptors, antibodies or other macromolecules. A detection method is used to determine the presence and extent of the ligand-receptor complexes formed, and this is usually determined electrochemically or through a fluorescence detection method. This type of analytic test can be used to test for the presence of target molecules in a sample that are known to bind to the receptor.

References

  1. ↑ Klotz, I.M. (1997). Ligand-Receptor Energetics: A Guide for the Perplexed. Wiley. ISBN   978-0-471-17626-8.
  2. ↑ Foreman, J.C.; Johansen, T., eds. (2003). Textbook of receptor pharmacology (2nd. ed.). Boca Raton, Fla.: CRC Press. ISBN   978-0-8493-1029-4.
  3. ↑ Walker, M.; Shah, H.H. (1997). Everything you should know about chelation therapy (4th ed.). New Canaan, Conn.: Keats Pub. ISBN   978-0-87983-730-3.
  4. ↑ Iron-Selective Chelators With Therapeutic Potential in Hider, Robert C.; Kong, Xiaole (2013). "Chapter 8. Iron: Effect of Overload and Deficiency". In Astrid Sigel, Helmut Sigel and Roland K. O. Sigel (ed.). Interrelations between Essential Metal Ions and Human Diseases. Metal Ions in Life Sciences. Vol. 13. Dordrecht: Springer. pp. 229–294. doi:10.1007/978-94-007-7500-8_8. ISBN   9789400774995. PMID   24470094.
  5. ↑ Miller, Marvin J. (1989). "Syntheses and therapeutic potential of hydroxamic acid-based siderophores and analogs". Chemical Reviews. 89 (7): 1563–1579. doi:10.1021/cr00097a011.
  6. ↑ Ahrland, S.; Chatt, J.; Davies, N.R. (1958). "The relative affinities of ligand atoms for acceptor molecules and ions". Quart. Rev. 12 (3): 265–276. doi:10.1039/QR9581200265.
  7. ↑ Farkas, Etelka; Buglyó, Péter (2017). "Chapter 8. Lead(II) Complexes of Amino Acids, Peptides, and Other Related Ligands of Biological Interest". In Astrid, S.; Helmut, S.; Sigel, R. K. O. (eds.). Lead: Its Effects on Environment and Health. Metal Ions in Life Sciences. Vol. 17. Berlin, Boston: de Gruyter. pp. 201–240. doi:10.1515/9783110434330-008. ISBN   9783110434330. PMID   28731301.
  8. ↑ Skoog, D.A; West, D.M.; Holler, J.F.; Crouch, S.R. (2004). Fundamentals of Analytical Chemistry (8th ed.). Thomson Brooks/Cole. ISBN   978-0-03-035523-3. Section 30E
  9. ↑ IUPAC , Compendium of Chemical Terminology , 2nd ed. (the "Gold Book") (1997). Online corrected version: (2006–) " selectivity coefficient, kA/B in ion exchange chromatography ". doi : 10.1351/goldbook.S05566.html
  10. ↑ Rice, N.M.; Irving, H. M. N. H.; Leonard, M.A (1993). "Nomenclature for liquid-liquid distribution (solvent extraction)". Pure Appl. Chem. IUPAC. 65 (11): 2373–2396. doi: 10.1351/pac199365112373 . S2CID   98514016.
  11. ↑ Rydberg, J.; Musikas, C; Choppin, G.R., eds. (2004). Solvent Extraction Principles and Practice ( (2nd. ed.). Boca Raton, Fla.: CRC Press. ISBN   978-0-8247-5063-3.
  12. ↑ Buck, R. P.; Linder, E. (1994). "Recommendations for nomenclature of ion-selective electrodes". Pure Appl. Chem. IUPAC. 66 (12): 2527–2536. doi: 10.1351/Pac199466122527 . S2CID   97126225.
  13. ↑ Florinel-Gabriel Bănică, Chemical Sensors and Biosensors: Fundamentals and Applications, John Wiley and Sons, Chichester, 2012, Print ISBN   978-0-470-71066-1
  14. ↑ Cattrall, R.W. (1997). Chemical sensors. Oxford University Press. ISBN   978-0-19-850090-2.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.