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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
pharmacology Pharmacology is a branch of medicine, biology 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 biochemi ...
, a ligand is a substance that forms a complex with a biomolecule 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 by binding to a
site Site most often refers to: * Archaeological site * Campsite, a place used for overnight stay in an outdoor area * Construction site * Location, a point or an area on the Earth's surface or elsewhere * Website, a set of related web pages, typi ...
on a target
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, respon ...
. 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. Binding occurs by
intermolecular force An intermolecular force (IMF) (or secondary force) is the force that mediates interaction between molecules, including the electromagnetic forces of attraction or repulsion which act between atoms and other types of neighbouring particles, e.g. a ...
s, such as
ionic bond Ionic bonding is a type of chemical bonding that involves the electrostatic attraction between oppositely charged ions, or between two atoms with sharply different electronegativities, and is the primary interaction occurring in ionic compoun ...
s,
hydrogen bond In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing ...
s and
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 t ...
s. The association or docking is actually reversible through dissociation. Measurably irreversible covalent bonding between a ligand and target molecule is atypical in biological systems. In contrast to the definition 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 ele ...
in metalorganic and
inorganic chemistry Inorganic chemistry deals with synthesis and behavior of inorganic and organometallic compounds. This field covers chemical compounds that are not carbon-based, which are the subjects of organic chemistry. The distinction between the two disc ...
, in biochemistry it is ambiguous whether the ligand generally binds at a
metal A metal (from Greek μέταλλον ''métallon'', "mine, quarry, metal") is a material that, when freshly prepared, polished, or fractured, shows a lustrous appearance, and conducts electricity and heat relatively well. Metals are typi ...
site, as is the case in
hemoglobin Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
. In general, the interpretation of ligand is contextual with regards to what sort of binding has been observed. Ligand binding to a receptor protein 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 lo ...
s,
inhibitor Inhibitor or inhibition may refer to: In biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...
s, activators, signaling lipids, and
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neur ...
s. The rate of binding is called affinity, 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 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 that is radiolabeled) that is used for diagnosis or for research-oriented study of the receptor systems of the body. In a neuroimaging application the radioligand is ...
s are
radioisotope A radionuclide (radioactive nuclide, radioisotope or radioactive isotope) is a nuclide that has excess nuclear energy, making it unstable. This excess energy can be used in one of three ways: emitted from the nucleus as gamma radiation; transferr ...
labeled compounds used
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
as
tracer Tracer may refer to: Science * Flow tracer, any fluid property used to track fluid motion * Fluorescent tracer, a substance such as 2-NBDG containing a fluorophore that is used for tracking purposes * Histochemical tracer, a substance used for tr ...
s in PET 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 and ...
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 (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 Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ...
or
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
. 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 activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
. Ligands that bind to a receptor but fail to activate the physiological response are receptor antagonists. Agonist binding to a receptor can be characterized both in terms of how much physiological response can be triggered (that is, the efficacy) 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'' ...
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 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 In chemistry, biochemistry, and pharmacology, a dissociation constant (K_D) 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 ...
(Kd) using methods such as
fluorescence quenching Quenching refers to any process which decreases the fluorescence intensity of a given substance. A variety of processes can result in quenching, such as excited state reactions, energy transfer, complex-formation and collisional quenching. As a co ...
, 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 Molar (nM = 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.


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 activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
, 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, biology 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 biochemi ...
, where
drugs A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhalat ...
that are non-selective tend to have more
adverse effects An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a " side effect", when judged to be secondary to a main or therapeutic effect. The term compl ...
, 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 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 G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
(GPCR) systems including cannabinoid, serotonin, oxytocin, and melanocortin receptor systems, and for GPCR- LIC systems ( D2 and 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 Raman spectroscopy () (named after Indian physicist C. V. Raman) is a spectroscopic technique typically used to determine vibrational modes of molecules, although rotational and other low-frequency modes of systems may also be observed. Raman s ...
* Fluorescence spectroscopy * Circular dichroism *
Nuclear magnetic resonance Nuclear magnetic resonance (NMR) is a physical phenomenon in which nuclei in a strong constant magnetic field are perturbed by a weak oscillating magnetic field (in the near field) and respond by producing an electromagnetic signal with a ...
*
Mass spectrometry Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a '' mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is u ...
* 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 Bio-layer interferometry (BLI) is an optical biosensing technology that analyzes biomolecular interactions in real-time without the need for fluorescent labeling. Alongside Surface Plasmon Resonance, BLI is one of few widely available label-free bi ...
, Coimmunopreciptation indirect ELISA, equilibrium dialysis, gel electrophoresis, far western blot, fluorescence polarization anisotropy, electron paramagnetic resonance, microscale thermophoresis, switchSENSE. 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 Computational chemistry is a branch of chemistry that uses computer simulation to assist in solving chemical problems. It uses methods of theoretical chemistry, incorporated into computer programs, to calculate the structures and properties of mo ...
. 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 The Human Proteome Folding Project (HPF) is a collaborative effort between New York University ( Bonneau Lab), the Institute for Systems Biology (ISB) and the University of Washington (Baker A baker is a tradesperson who bakes and sometime ...
,
Compute Against Cancer Compute Against Cancer is an initiative of Parabon Computation, Inc. powered by the Global Grid Exchange. The program provides cancer researchers access to supercomputing capabilities through Parabon’s Frontier Grid Platform. The Compute Against ...
and Folding@Home.


See also

*
Agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
*
Schild regression In pharmacology, Schild regression analysis, named for Heinz Otto Schild, is a tool for studying the effects of agonists and antagonists on the response caused by the receptor or on ligand-receptor binding. Dose-response curves can be constru ...
* Allosteric regulation *
Ki Database The Ki Database (or Ki DB) is a public domain database of published binding affinities (''K''i) of drugs and chemical compounds for receptors, neurotransmitter transporters, ion channels, and enzymes Enzymes () are proteins that act as ...
*
Docking@Home Docking@Home was a volunteer computing project hosted by the University of Delaware and running on the Berkeley Open Infrastructure for Network Computing (BOINC) software platform. It models protein-ligand In coordination chemistry, a l ...
* 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