Binding selectivity is defined with respect to the binding of
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...
s to a substrate forming a
complex
Complex commonly refers to:
* Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe
** Complex system, a system composed of many components which may interact with each ...
. Binding selectivity describes how a ligand may bind more preferentially to one receptor than another. A selectivity coefficient is the
equilibrium constant
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 ...
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
Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology and ...
and in
chemical separation processes.
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 constant
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 ...
s ''K''
AB and ''K''
AC.
[The constant used here are ''association'' constants. ''Dissociation'' constants are used in some contexts. A dissociation constant is the reciprocal of an association constant.]
:
+ B <=> AB; \mathit K_=\frac
:
+ C <=> AC; \mathit K_=\frac
represents the
concentration
In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', ''molar concentration'', '' number 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
:
+ C <=> + B; \mathit K_=\frac
=\frac
=\frac
It is easy to show that the same definition applies to complexes of a different stoichiometry, A
pB
q and A
pC
q. 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, ''K''
AB and ''K''
AC.
Applications
Biochemistry
In biochemistry the substrate is known as a receptor. A receptor is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
molecule, embedded in either the
plasma membrane or the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
of a cell, to which one or more specific kinds of signalling molecules may bind. A
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...
may be a
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
A ...
or another small molecule, such as a
neurotransmitter, a
hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are require ...
, 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
In chemistry, a non-covalent interaction differs from a covalent bond in that it does not involve the sharing of electrons, but rather involves more dispersed variations of electromagnetic interactions between molecules or within a molecule. The ...
, such as
hydrogen bonding or
Van der Waals force
In molecular physics, the van der Waals force is a distance-dependent interaction between atoms or molecules. Unlike ionic or covalent bonds, these attractions do not result from a chemical electronic bond; they are comparatively weak and th ...
s.
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
The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...
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 relationship
Quantitative may refer to:
* Quantitative research, scientific investigation of quantitative properties
* Quantitative analysis (disambiguation)
* Quantitative verse, a metrical system in poetry
* Statistics, also known as quantitative analysis ...
s (QSAR) led to the development of other agents such as
ranitidine
Ranitidine, sold under the brand name Zantac among others, is a medication used to decrease stomach acid production. It is commonly used in treatment of peptic ulcer disease, gastroesophageal reflux disease, and Zollinger–Ellison syndrome ...
.
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
Chelation therapy is a form of medical treatment in which a
chelating ligand
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 (multiple bonded) ligand and a single central metal atom. These ligands are ...
[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.] is used to selectively remove a metal from the body. When the metal exists as a divalent ion, such as with
lead
Lead is a chemical element with the symbol Pb (from the Latin ) and atomic number 82. It is a heavy metal that is denser than most common materials. Lead is soft and malleable, and also has a relatively low melting point. When freshly cu ...
, Pb
2+ or
mercury, Hg
2+ selectivity against
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...
, Ca
2+ and
magnesium
Magnesium is a chemical element with the symbol Mg and atomic number 12. It is a shiny gray metal having a low density, low melting point and high chemical reactivity. Like the other alkaline earth metals (group 2 of the periodic ta ...
, Mg
2+, is essential in order that the treatment does not remove essential metals.
Selectivity is determined by various factors. In the case of
iron overload
Iron overload or hemochromatosis (also spelled ''haemochromatosis'' in British English) indicates increased total accumulation of iron in the body from any cause and resulting organ damage. The most important causes are hereditary haemochromatos ...
, which may occur in individuals with β-
thalessemia who have received
blood transfusion
Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mo ...
s, the target metal ion is in the +3
oxidation state
In chemistry, the oxidation state, or oxidation number, is the hypothetical charge of an atom if all of its bonds to different atoms were fully ionic. It describes the degree of oxidation (loss of electrons) of an atom in a chemical compound. C ...
and so forms stronger complexes than the divalent ions. It also forms stronger complexes with oxygen-donor ligands than with nitrogen-donor ligands.
deferoxamine
Deferoxamine (DFOA), also known as desferrioxamine and sold under the brand name Desferal, is a medication that binds iron and aluminium. It is specifically used in iron overdose, hemochromatosis either due to multiple blood transfusions or an un ...
, a naturally occurring
siderophore
Siderophores (Greek: "iron carrier") are small, high-affinity iron- chelating compounds that are secreted by microorganisms such as bacteria and fungi. They help the organism accumulate iron. Although a widening range of siderophore functions is n ...
produced by the actinobacter ''
Streptomyces pilosus
''Streptomyces pilosus'' is a bacterium species from the genus of '' Streptomyces'' which has been isolated from soil in Rome in Italy.Deutsche Sammlung von Mikroorganismen und Zellkulturenbr>/ref> ''Streptomyces pilosus'' produces piloquinone ...
'' and was used initially as a chelation therapy agent. Synthetic siderophores such as
deferiprone
Deferiprone, sold under the brand name Ferriprox among others, is a medication that chelates iron and is used to treat iron overload in thalassaemia major. It was first approved and indicated for use in treating thalassaemia major in 1994 and h ...
and
deferasirox
Deferasirox, sold under the brand name Exjade & Asunra (in injectable form) & Oleptiss (Tablet formulation) both by Novartis among others, is an oral iron chelator. Its main use is to reduce chronic iron overload in patients who are receiving l ...
have been developed, using the known structure of deferoxamine as a starting point. Chelation occurs with the two oxygen atoms.
Wilson's disease
Wilson's disease is a genetic disorder in which excess copper builds up in the body. Symptoms are typically related to the brain and liver. Liver-related symptoms include vomiting, weakness, fluid build up in the abdomen, swelling of the legs, ...
is caused by a defect in
copper
Copper is a chemical element with the symbol Cu (from la, cuprum) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pinkis ...
metabolism which results in accumulation of copper metal in various organs of the body. The target ion in this case is divalent, Cu
2+. This ion is classified as borderline in the scheme of Ahrland, Chatt and Davies. 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
Penicillamine, sold under the brand name of Cuprimine among others, is a medication primarily used for the treatment of Wilson's disease. It is also used for people with kidney stones who have high urine cystine levels, rheumatoid arthritis, ...
, 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
Ethylenediaminetetraacetic acid (EDTA) is an aminopolycarboxylic acid with the formula H2N(CH2CO2H)2sub>2. This white, water-soluble solid is widely used to bind to iron (Fe2+/Fe3+) and calcium ions (Ca2+), forming water-soluble complexes ev ...
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,
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 coefficient
In the physical sciences, a partition coefficient (''P'') or distribution coefficient (''D'') is the ratio of concentrations of a compound in a mixture of two immiscible solvents at equilibrium. This ratio is therefore a comparison of the solub ...
s, which describe the equilibrium distribution of an
analyte
An analyte, component (in clinical chemistry), or chemical species is a substance or chemical constituent that is of interest in an analytical procedure. The purest substances are referred to as analytes, such as 24 karat gold, NaCl, water, etc. ...
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. The resolution of a chromatographic column, ''R''
S is related to the selectivity factor by:
:
where α is selectivity factor, ''N'' is the number of
theoretical plate A theoretical plate in many separation processes is a hypothetical zone or stage in which two phases, such as the liquid and vapor phases of a substance, establish an equilibrium with each other. Such equilibrium stages may also be referred to as a ...
s ''k''
A and ''k''
B are the
retention factor In chromatography, the retardation factor (''R'') is the fraction of an analyte
An analyte, component (in clinical chemistry), or chemical species is a substance or chemical constituent that is of interest in an analytical procedure. The purest ...
s 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
Gas chromatography (GC) is a common type of chromatography used in analytical chemistry for separating and analyzing compounds that can be vaporized without decomposition. Typical uses of GC include testing the purity of a particular substance, ...
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
Solvent extraction
Solvent extraction is used to extract individual
lanthanoid
The lanthanide () or lanthanoid () series of chemical elements comprises the 15 metallic chemical elements with atomic numbers 57–71, from lanthanum through lutetium. These elements, along with the chemically similar elements scandium and ytt ...
elements from the mixtures found in nature in ores such as
monazite
Monazite is a primarily reddish-brown phosphate mineral that contains rare-earth elements. Due to variability in composition, monazite is considered a group of minerals. The most common species of the group is monazite-(Ce), that is, the ceriu ...
. 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
Kerosene, paraffin, or lamp oil is a combustible hydrocarbon liquid which is derived from petroleum. It is widely used as a fuel in aviation as well as households. Its name derives from el, κηρός (''keros'') meaning "wax", and was regi ...
. Complete separation is effected by using a
countercurrent exchange
Countercurrent exchange is a mechanism occurring in nature and mimicked in industry and engineering, in which there is a crossover of some property, usually heat or some chemical, between two flowing bodies flowing in opposite directions to each ...
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.
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
![Sensing](https://upload.wikimedia.org/wikipedia/commons/a/a2/Sensing.png)
A potentiometric selectivity coefficient defines the ability of an
ion-selective electrode
An ion-selective electrode (ISE), also known as a specific ion electrode (SIE), is a transducer (or sensor) that converts the activity of a specific ion dissolved in a solution into an electrical potential. The voltage is theoretically dependent ...
to
distinguish one particular ion from others. The selectivity coefficient, K
B,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). For example, a
potassium
Potassium is the chemical element with the symbol K (from Neo-Latin ''kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmosph ...
ion-selective
membrane electrode utilizes the naturally occurring macrocyclic
antibiotic valinomycin
Valinomycin is a naturally occurring dodecadepsipeptide used in the transport of potassium and as an antibiotic. Valinomycin is obtained from the cells of several ''Streptomyces'' species, '' S. fulvissimus'' being a notable one.
It is a member o ...
. 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
A sensor is a device that produces an output signal for the purpose of sensing a physical phenomenon.
In the broadest definition, a sensor is a device, module, machine, or subsystem that detects events or changes in its environment and sends ...
,
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
Absorbance is defined as "the logarithm of the ratio of incident to transmitted radiant power through a sample (excluding the effects on cell walls)". Alternatively, for samples which scatter light, absorbance may be defined as "the negative lo ...
or, with greater sensitivity,
luminescence
Luminescence is spontaneous emission of light by a substance not resulting from heat; or "cold light".
It is thus a form of cold-body radiation. It can be caused by chemical reactions, electrical energy, subatomic motions or stress on a crys ...
. 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
*
Binding
*
Affinity
Affinity may refer to:
Commerce, finance and law
* Affinity (law), kinship by marriage
* Affinity analysis, a market research and business management technique
* Affinity Credit Union, a Saskatchewan-based credit union
* Affinity Equity Par ...
*
Functional selectivity
Functional selectivity (or “agonist trafficking”, “biased agonism”, “biased signaling”, "ligand bias" and “differential engagement”) is the ligand-dependent selectivity for certain signal transduction pathways relative to a referen ...
Notes
References
{{Pharmacology
Equilibrium chemistry
Pharmacodynamics