Ligand (biochemistry)

In biochemistry
Biochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms, including, but not limited to, living matter. Biochemistry governs all living organisms and living processes...

 and pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...

, a ligand (from the Latin ligandum, binding) is a substance that forms a complex
Complex (chemistry)
In chemistry, a coordination complex or metal complex, is an atom or ion , bonded to a surrounding array of molecules or anions, that are in turn known as ligands or complexing agents...

 with a biomolecule
A biomolecule is any molecule that is produced by a living organism, including large polymeric molecules such as proteins, polysaccharides, lipids, and nucleic acids as well as small molecules such as primary metabolites, secondary metabolites, and natural products...

 to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site
Binding site
In biochemistry, a binding site is a region on a protein, DNA, or RNA to which specific other molecules and ions—in this context collectively called ligands—form a chemical bond...

 on a target protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...


The binding occurs by intermolecular force
Intermolecular force
Intermolecular forces are forces of attraction or repulsion which act between neighboring particles: atoms, molecules or ions. They are weak compared to the intramolecular forces, the forces which keep a molecule together...

s, such as ionic bond
Ionic bond
An ionic bond is a type of chemical bond formed through an electrostatic attraction between two oppositely charged ions. Ionic bonds are formed between a cation, which is usually a metal, and an anion, which is usually a nonmetal. Pure ionic bonding cannot exist: all ionic compounds have some...

s, hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...

s and van der Waals force
Van der Waals force
In physical chemistry, the van der Waals force , named after Dutch scientist Johannes Diderik van der Waals, is the sum of the attractive or repulsive forces between molecules other than those due to covalent bonds or to the electrostatic interaction of ions with one another or with neutral...

s. The docking (association) is usually reversible (dissociation). Actual irreversible covalent binding between a ligand and its target molecule is rare in biological systems. In contrast to the meaning in metalorganic and inorganic chemistry
Inorganic chemistry
Inorganic chemistry is the branch of chemistry concerned with the properties and behavior of inorganic compounds. This field covers all chemical compounds except the myriad organic compounds , which are the subjects of organic chemistry...

, it is irrelevant whether the ligand actually binds at a metal
A metal , is an element, compound, or alloy that is a good conductor of both electricity and heat. Metals are usually malleable and shiny, that is they reflect most of incident light...

 site, as is the case in hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...


Ligand binding to a receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...

 alters the chemical conformation, which is the three dimensional shape of the receptor protein. The conformational state of a receptor protein determines the functional state of a receptor. Ligands include substrate
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...

s, inhibitor
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...

s, activator
Activator may mean:* Activator , a DNA-binding protein that regulates one or more genes by increasing the rate of transcription* Activator , a type of effector that increases the rate of enzyme mediated reactions...

s, and neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...

s. The tendency or strength of binding is called affinity.

A radioligand is a radioactive biochemical substance that is used for diagnosis or for research-oriented study of the receptor systems of the body....

s are radioisotope labeled compounds and used in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...

 as tracer
Tracer may refer to:* Histochemical tracer, a substance used for tracing purposes in histochemistry, the study of the composition of cells and tissues...

s in PET
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...

 studies and for in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...

 binding studies.

Receptor/ligand binding affinity

The interaction of most ligands with their binding sites can be characterized in terms of a binding affinity. In general, high affinity ligand binding results from greater intermolecular force between the ligand and its receptor while low affinity ligand binding involves less intermolecular force between the ligand and its receptor. In general, high affinity binding involves a longer residence time for the ligand at its receptor binding site than is the case for low affinity binding. High affinity binding of ligands to receptors is often physiologically important when some of the binding energy can be used to cause a conformational change in the receptor, resulting in altered behavior of an associated ion channel
Ligand-gated ion channel
Ligand-gated ion channels are one type of ionotropic receptor or channel-linked receptor. They are a group of transmembrane ion channels that are opened or closed in response to the binding of a chemical messenger , such as a neurotransmitter.The binding site of endogenous ligands on LGICs...

 or enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

A ligand that can bind to a receptor, alter the function of the receptor and trigger a physiological response is called an agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...

 for that receptor. Agonist binding to a receptor can be characterized both in terms of how much physiological response can be triggered and in terms of the concentration
In chemistry, concentration is defined as the abundance of a constituent divided by the total volume of a mixture. Four types can be distinguished: mass concentration, molar concentration, number concentration, and volume concentration...

 of the agonist that is required to produce the physiological response. High-affinity ligand binding implies that a relatively low concentration of a ligand is adequate to maximally occupy a ligand-binding site and trigger a physiological response. Low-affinity binding implies that a relatively high concentration of a ligand is required before the binding site is maximally occupied and the maximum physiological response to the ligand is achieved. In the example shown to the right, two different ligands bind to the same receptor binding site. Only one of the agonists shown can maximally stimulate the receptor and, thus, can be defined as a "full agonist". An agonist that can only partially activate the physiological response is called a "partial agonist". Ligands that bind to a receptor but fail to activate the physiological response are receptor "antagonists
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...

". In this example, the concentration at which the full agonist (red curve) can half-maximally activate the receptor is about 5 x 10−9 Molar (nM = nano
Nano- is a prefix meaning a billionth. Used primarily in the metric system, this prefix denotes a factor of 10−9 or . It is frequently encountered in science and electronics for prefixing units of time and length, such as 30 nanoseconds , 100 nanometres or in the case of electrical capacitance,...

In the example shown to the left, ligand-binding curves are shown for two ligands with different binding affinities. Ligand binding is often characterized in terms of the concentration of ligand at which half of the receptor binding sites are occupied, known as the dissociation constant
Dissociation constant
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 reversibly into smaller components, as when a complex falls apart into its component molecules, or when a salt splits up into...

 (Kd). The ligand illustrated by the red curve has a higher binding affinity and smaller Kd than the ligand illustrated by the green curve. If these two ligands were present at the same time, more of the higher-affinity ligand would be bound to the available receptor binding sites. This is how carbon monoxide
Carbon monoxide
Carbon monoxide , also called carbonous oxide, is a colorless, odorless, and tasteless gas that is slightly lighter than air. It is highly toxic to humans and animals in higher quantities, although it is also produced in normal animal metabolism in low quantities, and is thought to have some normal...

 can compete with oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...

 in binding to hemoglobin, resulting in carbon monoxide poisoning
Carbon monoxide poisoning
Carbon monoxide poisoning occurs after enough inhalation of carbon monoxide . Carbon monoxide is a toxic gas, but, being colorless, odorless, tasteless, and initially non-irritating, it is very difficult for people to detect...


Binding affinity is most commonly determined using a radiolabeled ligand, known as hot ligand. Homologous competitive binding experiments involve binding-site competition between a hot ligand and a cold ligand (untagged ligand).
Non labelled methods such as surface plasmon resonance
Surface plasmon resonance
The excitation of surface plasmons by light is denoted as a surface plasmon resonance for planar surfaces or localized surface plasmon resonance for nanometer-sized metallic structures....

 and dual polarisation interferometry
Dual Polarisation Interferometry
Dual polarization interferometry is an analytical technique that can probe molecular scale layers adsorbed to the surface of a waveguide by using the evanescent wave of a laser beam confined to the waveguide...

 can also quantify the affinity from concentration based assays but also from the kinetics of association and dissociation, and, in the later case, the conformational change induced upon binding. Recently, Microscale Thermophoresis
Microscale Thermophoresis
Microscale Thermophoresis is a technology for the analysis of biomolecules. Microscale Thermophoresis is the directed movement of particles in a microscopic temperature gradient...

 (MST), an immobilization-free method was developed. This method allows to determine the binding affinity without any limitation to the ligand's molecular weight.

For the use of statistical mechanics
Statistical mechanics
Statistical mechanics or statistical thermodynamicsThe terms statistical mechanics and statistical thermodynamics are used interchangeably...

 in a quantitative study of the
ligand-receptor binding affinity, see the comprehensive article
on the configuration integral.

Drug potency and binding affinity

Binding affinity data alone does not determine the overall potency of a drug. Potency is a result of the complex interplay of both the binding affinity and the ligand efficacy. Ligand efficacy refers to the ability of the ligand to produce a biological response upon binding to the target receptor and the quantitative magnitude of this response. This response may be as an agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...

, antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...

, or inverse agonist
Inverse agonist
In the field of pharmacology, an inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist....

, depending on the physiological response produced.

Selective and non-selective

Selective ligands have a tendency to bind to a very limited types of receptors, whereas non-selective ligands bind to several types of receptors. This plays an important role in pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...

, where drugs
Destroy Rebuild Until God Shows are an American post-hardcore band formed in 2010. They released their debut self-titled album on February 22, 2011.- Formation :...

 that are non-selective tend to have more adverse effects, because they bind to several other receptors in addition to the one generating the desired effect.

See also

  • Agonist
    An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...

  • Schild regression
    Schild regression
    Schild regression analysis, named for Heinz Otto Schild, is a useful tool for studying the effects of agonists and antagonists on the cellular response caused by the receptor or on ligand-receptor binding....

  • Allosteric regulation
    Allosteric regulation
    In biochemistry, allosteric regulation is the regulation of an enzyme or other protein by binding an effector molecule at the protein's allosteric site . Effectors that enhance the protein's activity are referred to as allosteric activators, whereas those that decrease the protein's activity are...

  • Ki Database
    Ki Database
    The Ki Database is a public domain database of published binding affinities of drugs and chemical compounds for receptors, neurotransmitter transporters, ion channels, and enzymes...

  • Docking@Home
    Docking@Home is a distributed computing project hosted by the University of Delaware and running on the Berkeley Open Infrastructure for Network Computing software platform. It models protein-ligand docking using the CHARMM program. The ultimate aim is the development of new pharmaceutical...

    GPUGRID is a distributed computing project hosted by Pompeu Fabra University and running on the Berkeley Open Infrastructure for Network Computing software platform...

External links

  • BindingDB, a public database of measured protein-ligand binding affinities.
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