ligand (biochemistry)
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In
biochemistry
biochemistry
and
pharmacology Pharmacology is a branch of medicine and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemical or physi ...
, a ligand is a
substance Substance may refer to: * Substance (Jainism), a term in Jain ontology to denote the base or owner of attributes * Chemical substance, a material with a definite chemical composition * Matter, anything that has mass and takes up space * Substance th ...
that forms a
complex The UCL Faculty of Mathematical and Physical Sciences is one of the 11 constituent faculties of University College London , mottoeng = Let all come who by merit deserve the most reward , established = , type = Public university, Public rese ...
with a
biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a Nobel Prize in Chemistry, Nobel Prize i ...
to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a molecule which produces a
signal In signal processing Signal processing is an electrical engineering subfield that focuses on analysing, modifying, and synthesizing signals such as audio signal processing, sound, image processing, images, and scientific measurements. Sig ...
by binding to a
site Site most often refers to: * Archaeological site An archaeological site is a place (or group of physical sites) in which evidence of past activity is preserved (either prehistoric Prehistory, also known as pre-literary history, is the perio ...
on a target
protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing m ...

protein
. The binding typically results in a change of
conformational isomerism In chemistry Chemistry is the scientific discipline involved with Chemical element, elements and chemical compound, compounds composed of atoms, molecules and ions: their composition, structure, properties, behavior and the changes they und ...
(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 In molecular biology, the term double helix refers to the structure formed by double-stranded molecules of nucleic acids such as DNA. The double helical structure of a nucleic acid complex arises as a consequence of its secondary structure ...
. The relationship between ligand and binding partner is a function of charge, hydrophobicity, and molecular structure. The instance of binding occurs over an infinitesimal range of time and space, so the
rate constantIn chemical kinetics a reaction rate constant or reaction rate coefficient, ''k'', quantifies the rate and direction of a chemical reaction. For a reaction between reactants A and B to form product C :''a'' A + ''b'' B → ''c'' C th ...
is usually a very small number. Binding occurs by
intermolecular force Intermolecular forces (IMF) (or secondary forces) are the forces which mediate interaction between molecules, including forces of attraction or repulsion which act between atoms and other types of neighboring particles, e.g. atom An atom is the ...

intermolecular force
s, such as
ionic bond Ionic bonding is a type of chemical bond A chemical bond is a lasting attraction between atoms, ions or molecules that enables the formation of chemical compounds. The bond may result from the Coulomb's law, electrostatic force of attraction be ...
s,
hydrogen bond A hydrogen bond (or H-bond) is a primarily Electrostatics, electrostatic force of attraction between a hydrogen Hydrogen is the chemical element Image:Simple Periodic Table Chart-blocks.svg, 400px, Periodic table, The periodic table of ...

hydrogen bond
s and
Van der Waals force Microfiber cloth makes use of London-dispersion force to remove dirt without scratches. In molecular physics Molecular physics is the study of the physical properties of molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling micr ...
s. The association or docking is actually reversible through dissociation. Measurably irreversible
covalent A covalent bond is a chemical bond A chemical bond is a lasting attraction between atom An atom is the smallest unit of ordinary matter In classical physics and general chemistry, matter is any substance that has mass and takes ...

covalent
bonding between a ligand and target molecule is atypical in biological systems. In contrast to the definition of
ligand In coordination chemistry A coordination complex consists of a central atom An atom is the smallest unit of ordinary matter In classical physics and general chemistry, matter is any substance that has mass and takes up space by havi ...
in
metalorganic Metal-organic compounds (jargon: metalorganics, metallo-organics) are a class of chemical compounds that contain metals and organic ligands, which confer solubility in organic solvents or volatility. Compounds with these properties find application ...
and
inorganic chemistry#REDIRECT Inorganic chemistry features unusual bonding B: Caesium chloride Caesium chloride or cesium chloride is the inorganic compound with the formula Caesium, CsChloride, Cl. This colorless salt is an important source of caesium ions in a var ...
, in biochemistry it is ambiguous whether the ligand generally binds at a
metal A metal (from Ancient Greek, Greek μέταλλον ''métallon'', "mine, quarry, metal") is a material that, when freshly prepared, polished, or fractured, shows a lustrous appearance, and conducts Electrical resistivity and conductivity, el ...

metal
site, as is the case in
hemoglobin Hemoglobin, or haemoglobin ( spelling differences) (Greek αἷμα (haîma, “blood”) + -in) + -o- + globulin (from Latin globus (“ball, sphere”) + -in) (), abbreviated Hb or Hgb, is the iron Iron () is a chemical element with Symbol ( ...

hemoglobin
. In general, the interpretation of ligand is contextual with regards to what sort of binding has been observed. Ligand binding to a
receptor protein 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 biolo ...
alters the conformation by affecting the three-dimensional shape orientation. The conformation of a receptor protein composes the functional state. Ligands include
substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached **Substrate (locomotion), the surface over which an organism loco ...
s, inhibitors, activators, signaling lipids, and
neurotransmitter A neurotransmitter is a signaling molecule In biology, cell signaling (cell signalling in British English), or cell-cell communication, governs the basic activities of cells and coordinates multiple-cell actions. A signal is an entity that ...
s. The rate of binding is called
affinity Affinity may refer to: Commerce, finance and law * Affinity (law) In law and in cultural anthropology Cultural anthropology is a branch of anthropology Anthropology is the Science, scientific study of humanity, concerned with human ...
, and this measurement typifies a tendency or strength of the effect. Binding affinity is actualized not only by host–guest interactions, but also by solvent effects that can play a dominant,
steric Steric effects are nonbonding interactions that influence the shape (conformational isomerism, conformation) and chemical reaction, reactivity of ions and molecules. Steric effects complement electronic effects, which dictate the shape and reacti ...
role which drives non-covalent binding in solution. The solvent provides a chemical environment for the ligand and receptor to adapt, and thus accept or reject each other as partners.
Radioligand A radioligand is a radioactive biochemical substance (in particular, a ligand (biochemistry), ligand that is radioactive tracer, radiolabeled) that is used for diagnosis or for research-oriented study of the receptor (biochemistry), receptor systems ...
s are
radioisotope A radionuclide (radioactive nuclide, radioisotope or radioactive isotope) is a nuclide A nuclide (or nucleide, from nucleus, also known as nuclear species) is a class of atoms characterized by their number of proton A proton is a subatomic par ...
labeled compounds used
in vivo Studies Study or studies may refer to: General * Education **Higher education * Clinical trial * Experiment * Observational study * Research * Study skills, abilities and approaches applied to learning Other * Study (art), a drawing or series ...
as tracers in
PET A pet is an animal kept primarily for company, protection or entertainment. Pet or PET may also refer to: People * Petula Clark (born 1932), English singer, actress and composer * Pierre Elliott Trudeau (1919–2000), nicknamed PET, former Pri ...
studies and for
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...

in vitro
binding studies.


Receptor/ligand binding affinity

The interaction of ligands with their binding sites can be characterized in terms of a binding affinity. In general, high-affinity ligand binding results from greater attractive forces between the ligand and its receptor while low-affinity ligand binding involves less attractive force. In general, high-affinity binding results in a higher occupancy of the receptor by its ligand than is the case for low-affinity binding; the
residence time The residence time of a fluid parcelIn fluid dynamics In physics and engineering, fluid dynamics is a subdiscipline of fluid mechanics that describes the flow of fluids—liquids and gases. It has several subdisciplines, including aerodynamics ...
(lifetime of the receptor-ligand complex) does not correlate. 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 for example of an associated
ion channel s (typically four per channel), 2 - outer vestibule, 3 - Potassium channel#Selectivity filter, selectivity filter, 4 - diameter of selectivity filter, 5 - phosphorylation site, 6 - cell membrane. Ion channels are pore-forming membrane proteins that ...
or
enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates int ...

enzyme
. A ligand that can bind to and alter the function of the receptor that triggers a physiological response is called a receptor
agonist An agonist is a chemical that binds to a receptor and activates the receptor to produce a biological response. In contrast, an antagonist blocks the action of the agonist, while an inverse agonist causes an action opposite to that of the agonist ...

agonist
. Ligands that bind to a receptor but fail to activate the physiological response are receptor
antagonists An antagonist is a character in a story who is presented as the chief foe of the protagonist 200px, Shakespeare's '' Hamlet, Prince of Denmark.'' William Morris Hunt, oil on canvas, c. 1864 A protagonist () is the main character of a story. T ...
. Agonist binding to a receptor can be characterized both in terms of how much physiological response can be triggered (that is, the
efficacy Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as ''effectiveness Effectiveness is the capability of producing a desired result or the ability to produce desired output. When ...
) and in terms of 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'', an ...

concentration
of the agonist that is required to produce the physiological response (often measured as EC50, the concentration required to produced the half-maximal 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. Receptor affinity is measured by an inhibition constant or Ki value, the concentration required to occupy 50% of the receptor. Ligand affinities are most often measured indirectly as an
IC50
IC<sub>50</sub>
value from a competition binding experiment where the concentration of a ligand required to displace 50% of a fixed concentration of reference ligand is determined. The Ki value can be estimated from IC50 through the Cheng Prusoff equation. Ligand affinities can also be measured directly as a dissociation constant (Kd) using methods such as fluorescence quenching, isothermal titration calorimetry or surface plasmon resonance. Low-affinity binding (high Ki level) 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''. In this example, the concentration at which the full agonist (red curve) can half-maximally activate the receptor is about 5 x 10−9 Concentration#Molarity, Molar (nM = Nano-, nanomolar). Binding affinity is most commonly determined using a radiolabeled ligand, known as a tagged ligand. ''Homologous competitive binding experiments'' involve binding competition between a tagged ligand and an untagged ligand. Real-time based methods, which are often label-free, such as surface plasmon resonance, dual-polarization interferometry and multi-parametric surface plasmon resonance (MP-SPR) can not only quantify the affinity from concentration based assays; but also from the kinetics of association and dissociation, and in the later cases, the conformational change induced upon binding. MP-SPR also enables measurements in high saline dissociation buffers thanks to a unique optical setup. Microscale thermophoresis (MST), an immobilization-free method was developed. This method allows the determination of the binding affinity without any limitation to the ligand's molecular weight. For the use of statistical mechanics in a quantitative study of the ligand-receptor binding affinity, see the comprehensive article on the configurational Partition function (statistical mechanics), partition function.


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 and activates the receptor to produce a biological response. In contrast, an antagonist blocks the action of the agonist, while an inverse agonist causes an action opposite to that of the agonist ...

agonist
, Receptor antagonist, antagonist, or inverse agonist, depending on the physiological response produced.


Selective and non-selective

Selective ligands have a tendency to bind to very limited kinds of receptor, whereas non-selective ligands bind to several types of receptors. This plays an important role in
pharmacology Pharmacology is a branch of medicine and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemical or physi ...
, where drugs 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.


Hydrophobic ligands

For hydrophobic ligands (e.g. PIP2) in complex with a hydrophobic protein (e.g. lipid-gated ion channels) determining the affinity is complicated by non-specific hydrophobic interactions. Non-specific hydrophobic interactions can be overcome when the affinity of the ligand is high. For example, PIP2 binds with high affinity to PIP2 gated ion channels.


Bivalent ligand

Bivalent ligands consist of two drug-like molecules (pharmacophores or ligands) connected by an inert linker. There are various kinds of bivalent ligands and are often classified based on what the pharmacophores target. Homobivalent ligands target two of the same receptor types. Heterobivalent ligands target two different receptor types. Bitopic ligands target an orthosteric binding sites and allosteric binding sites on the same receptor. In scientific research, bivalent ligands have been used to study GPCR oligomer, receptor dimers and to investigate their properties. This class of ligands was pioneered by Philip S. Portoghese and coworkers while studying the opioid receptor system. Bivalent ligands were also reported early on by Micheal Conn and coworkers for the gonadotropin-releasing hormone receptor. Since these early reports, there have been many bivalent ligands reported for various G protein-coupled receptor (GPCR) systems including cannabinoid, serotonin, oxytocin, and melanocortin receptor systems, and for G protein–coupled receptor, GPCR-Ligand-gated ion channel, LIC systems (Dopamine receptor D2, D2 and Nicotinic acetylcholine receptor, nACh receptors). Bivalent ligands usually tend to be larger than their monovalent counterparts, and therefore, not 'drug-like' as in Lipinski's rule of five. Many believe this limits their applicability in clinical settings. In spite of these beliefs, there have been many ligands that have reported successful pre-clinical animal studies. Given that some bivalent ligands can have many advantages compared to their monovalent counterparts (such as tissue selectivity, increased binding affinity, and increased potency or efficacy), bivalents may offer some clinical advantages as well.


Mono- and polydesmic ligands

Ligands of proteins can be characterized also by the number of protein chains they bind. “Monodesmic” ligands (μόνος: single, δεσμός: binding) are ligands that bind a single protein chain, while "polydesmic” ligands (πολοί: many) are frequent in protein complexes, and are ligands that bind more than one protein chain, typically in or near protein interfaces. Recent research shows that the type of ligands and binding site structure has profound consequences for the evolution, function, allostery and folding of protein compexes.


Privileged scaffold

A privileged scaffold is a molecular framework or chemical moiety that is statistically recurrent among known drugs or among a specific array of biologically active compounds. These privileged elements can be used as a basis for designing new active biological compounds or compound libraries.


Methods used to study binding

Main methods to study protein–ligand interactions are principal hydrodynamic and calorimetric techniques, and principal spectroscopic and structural methods such as *Fourier transform spectroscopy *Raman spectroscopy *Fluorescence spectroscopy *Circular dichroism *Nuclear magnetic resonance *Mass spectrometry *Atomic force microscope *Paramagnetic probes *Dual polarisation interferometry *Multi-parametric surface plasmon resonance *Ligand binding assay and radioligand binding assay Other techniques include: fluorescence intensity, bimolecular fluorescence complementation, FRET (fluorescent resonance energy transfer) / FRET quenching surface plasmon resonance, bio-layer interferometry, Coimmunopreciptation indirect ELISA, equilibrium dialysis, gel electrophoresis, far western blot, fluorescence polarization anisotropy, electron paramagnetic resonance, microscale thermophoresis The dramatically increased computing power of supercomputers and personal computers has made it possible to study protein–ligand interactions also by means of computational chemistry. For example, a worldwide grid of well over a million ordinary PCs was harnessed for cancer research in the project grid.org, which ended in April 2007. Grid.org has been succeeded by similar projects such as World Community Grid, Human Proteome Folding Project, Compute Against Cancer and Folding@Home.


See also

* Agonist * Schild regression * Allosteric regulation * Ki Database * Docking@Home * GPUGRID.net * DNA binding ligand * BindingDB * SAMPL Challenge


References


External links


BindingDB
a public database of measured protein-ligand binding affinities.
BioLiP
a comprehensive database for ligand-protein interactions. {{DEFAULTSORT:Ligand (Biochemistry) Biomolecules Cell signaling Chemical bonding Proteins Ligands (biochemistry),