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56-404: Targeting ligands that bind to receptors characteristic of intravascular diseases can be conjugated to microbubbles , enabling the microbubble complex to accumulate selectively in areas of interest, such as diseased or abnormal tissues. This form of molecular imaging, known as targeted contrast-enhanced ultrasound, will only generate a strong ultrasound signal if targeted microbubbles bind in

112-444: 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,

168-493: 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 substrates , inhibitors , activators , signaling lipids , and neurotransmitters . 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

224-469: 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

280-415: A certain disease state, or identify particular cells in the area of interest. Untargeted contrast-enhanced ultrasound is currently applied in echocardiography and radiology . Targeted contrast-enhanced ultrasound is being developed for a variety of medical applications. Untargeted microbubbles like Optison and Levovist are currently used in echocardiography. In addition, SonoVue ultrasound contrast agent

336-478: 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. Radioligands are radioisotope labeled compounds used in vivo as tracers in PET studies and for in vitro binding studies. The interaction of ligands with their binding sites can be characterized in terms of

392-408: A fluid has strong implications for its dynamics. Most notably, the propagation of sound is dependent on the compressibility of the medium. Compressibility is an important factor in aerodynamics . At low speeds, the compressibility of air is not significant in relation to aircraft design, but as the airflow nears and exceeds the speed of sound , a host of new aerodynamic effects become important in

448-420: A great deal of energy in a reversible process and this greatly reduces the thermodynamic temperature of hypersonic gas decelerated near the aerospace object. Ions or free radicals transported to the object surface by diffusion may release this extra (nonthermal) energy if the surface catalyzes the slower recombination process. For ordinary materials, the bulk compressibility (sum of the linear compressibilities on

504-499: 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 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

560-400: A ligand and target molecule is atypical in biological systems. In contrast to the definition of ligand in metalorganic and inorganic chemistry , in biochemistry it is ambiguous whether the ligand generally binds at a metal site, as is the case in hemoglobin . In general, the interpretation of ligand is contextual with regards to what sort of binding has been observed. Ligand binding to

616-500: A ligand required to displace 50% of a fixed concentration of reference ligand is determined. The K i value can be estimated from IC 50 through the Cheng Prusoff equation . Ligand affinities can also be measured directly as a dissociation constant (K d ) using methods such as fluorescence quenching , isothermal titration calorimetry or surface plasmon resonance . Low-affinity binding (high K i level) implies that

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672-416: A limited sensitivity . When specifically looking for a defect such as this, small air bubbles can be used as a contrast medium and injected intravenously, where they travel to the right side of the heart. The test would be positive for an abnormal communication if the bubbles are seen passing into the left side of the heart. (Normally, they would exit the heart through the pulmonary artery and be stopped by

728-481: A lipid monolayer shell with a perfluorocarbon gas core. The lipid shell is also covered with a polyethylene glycol (PEG) layer. PEG prevents microbubble aggregation and makes the microbubble more non-reactive. It temporarily "hides" the microbubble from the immune system uptake, increasing the amount of circulation time, and hence, imaging time. In addition to the PEG layer, the shell is modified with molecules that allow for

784-402: A material is inversely proportional to its volume, it can be shown that in both cases For instance, for an ideal gas , Consequently, the isothermal compressibility of an ideal gas is The ideal gas (where the particles do not interact with each other) is an abstraction. The particles in real materials interact with each other. Then, the relation between the pressure, density and temperature

840-465: A real gas. The deviation from ideal gas behavior tends to become particularly significant (or, equivalently, the compressibility factor strays far from unity) near the critical point , or in the case of high pressure or low temperature. In these cases, a generalized compressibility chart or an alternative equation of state better suited to the problem must be utilized to produce accurate results. The Earth sciences use compressibility to quantify

896-423: 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

952-407: 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 K i value, the concentration required to occupy 50% of the receptor. Ligand affinities are most often measured indirectly as an IC 50 value from a competition binding experiment where the concentration of

1008-532: A result of the changes in airflow from an incompressible fluid (similar in effect to water) to a compressible fluid (acting as a gas) as the speed of sound is approached. There are two effects in particular, wave drag and critical mach . One complication occurs in hypersonic aerodynamics, where dissociation causes an increase in the "notional" molar volume because a mole of oxygen, as O 2 , becomes 2 moles of monatomic oxygen and N 2 similarly dissociates to 2 N. Since this occurs dynamically as air flows over

1064-450: A small bolus. Microbubbles theoretically travel through the circulatory system, eventually finding their respective targets and binding specifically. Ultrasound waves can then be directed on the area of interest. If a sufficient number of microbubbles have bound in the area, their compressible gas cores oscillate in response to the high frequency sonic energy field, as described in the ultrasound article. The targeted microbubbles also reflect

1120-504: 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

1176-462: A unique echo that stands in stark contrast to the surrounding tissue due to the orders of magnitude mismatch between microbubble and tissue echogenicity. The ultrasound system converts the strong echogenicity into a contrast-enhanced image of the area of interest, revealing the location of the bound microbubbles. Detection of bound microbubbles may then show that the area of interest is expressing that particular molecular marker, which can be indicative of

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1232-454: 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 . Binding affinity data alone does not determine

1288-459: 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 . Compressibility In thermodynamics and fluid mechanics , the compressibility (also known as

1344-401: Is volume and p is pressure. The choice to define compressibility as the negative of the fraction makes compressibility positive in the (usual) case that an increase in pressure induces a reduction in volume. The reciprocal of compressibility at fixed temperature is called the isothermal bulk modulus . The specification above is incomplete, because for any object or system the magnitude of

1400-413: Is as safe as in the adult population. An echocardiogram is a study of the heart using ultrasound. A bubble echocardiogram is an extension of this that uses simple air bubbles as a contrast medium during this study and often has to be requested specifically. Although colour Doppler can be used to detect abnormal flows between the chambers of the heart (e.g., persistent (patent) foramen ovale ), it has

1456-405: Is defined as where p is the pressure of the gas, T is its temperature , and V m {\displaystyle V_{m}} is its molar volume , all measured independently of one another. In the case of an ideal gas, the compressibility factor Z is equal to unity, and the familiar ideal gas law is recovered: Z can, in general, be either greater or less than unity for

1512-418: Is incomplete, both beta (the volume/pressure differential ratio) and the differential, constant pressure heat capacity greatly increases. For moderate pressures, above 10,000 K the gas further dissociates into free electrons and ions. Z for the resulting plasma can similarly be computed for a mole of initial air, producing values between 2 and 4 for partially or singly ionized gas. Each dissociation absorbs

1568-404: Is known as the equation of state denoted by some function F {\displaystyle F} . The Van der Waals equation is an example of an equation of state for a realistic gas. Knowing the equation of state, the compressibility can be determined for any substance. The speed of sound is defined in classical mechanics as: It follows, by replacing partial derivatives , that

1624-405: 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 or enzyme . A ligand that can bind to and alter the function of the receptor that triggers a physiological response is called a receptor agonist . Ligands that bind to a receptor but fail to activate

1680-400: Is used in radiology for lesion characterization. On top of the strengths mentioned in the medical sonography entry, contrast-enhanced ultrasound adds these additional advantages: In addition to the weaknesses mentioned in the medical sonography entry, contrast-enhanced ultrasound has the following disadvantages: Ligand (biochemistry) In biochemistry and pharmacology ,

1736-413: The coefficient of compressibility or, if the temperature is held constant, the isothermal compressibility ) is a measure of the instantaneous relative volume change of a fluid or solid as a response to a pressure (or mean stress ) change. In its simple form, the compressibility κ {\displaystyle \kappa } (denoted β in some fields) may be expressed as where V

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1792-456: The isentropic (or adiabatic ) compressibility by a few relations: where γ is the heat capacity ratio , α is the volumetric coefficient of thermal expansion , ρ = N / V is the particle density, and Λ = ( ∂ P / ∂ T ) V {\displaystyle \Lambda =(\partial P/\partial T)_{V}} is the thermal pressure coefficient . In an extensive thermodynamic system,

1848-409: The ability of a soil or rock to reduce in volume under applied pressure. This concept is important for specific storage , when estimating groundwater reserves in confined aquifers . Geologic materials are made up of two portions: solids and voids (or same as porosity ). The void space can be full of liquid or gas. Geologic materials reduce in volume only when the void spaces are reduced, which expel

1904-436: The aerospace object, it is convenient to alter the compressibility factor Z , defined for an initial 30 gram moles of air, rather than track the varying mean molecular weight, millisecond by millisecond. This pressure dependent transition occurs for atmospheric oxygen in the 2,500–4,000 K temperature range, and in the 5,000–10,000 K range for nitrogen. In transition regions, where this pressure dependent dissociation

1960-407: The application of statistical mechanics shows that the isothermal compressibility is also related to the relative size of fluctuations in particle density: where μ is the chemical potential . The term "compressibility" is also used in thermodynamics to describe deviations of the thermodynamic properties of a real gas from those expected from an ideal gas . The compressibility factor

2016-607: The area of interest. Targeted contrast-enhanced ultrasound may have many applications in both medical diagnostics and medical therapeutics. However, the targeted technique has not yet been approved by the FDA for clinical use in the United States. Contrast-enhanced ultrasound is regarded as safe in adults, comparable to the safety of MRI contrast agents , and better than radiocontrast agents used in contrast CT scans . The more limited safety data in children suggests that such use

2072-446: The area of interest. When microbubbles in the blood flow past the imaging window, the microbubbles' compressible gas cores oscillate in response to the high frequency sonic energy field, as described in the ultrasound article. The microbubbles reflect a unique echo that stands in stark contrast to the surrounding tissue due to the orders of magnitude mismatch between microbubble and tissue echogenicity. The ultrasound system converts

2128-493: The attachment of ligands that bind certain receptors . These ligands are attached to the microbubbles using carbodiimide , maleimide , or biotin-streptavidin coupling. Biotin-streptavidin is the most popular coupling strategy because biotin's affinity for streptavidin is very strong and it is easy to label the ligands with biotin. Currently, these ligands are monoclonal antibodies produced from animal cell cultures that bind specifically to receptors and molecules expressed by

2184-410: The clinic today) and targeted (under preclinical development). The two methods slightly differ from each other. Untargeted microbubbles, such as the aforementioned SonoVue, Optison, or Levovist, are injected intravenously into the systemic circulation in a small bolus. The microbubbles will remain in the systemic circulation for a certain period of time. During that time, ultrasound waves are directed on

2240-416: The compressibility depends strongly on whether the process is isentropic or isothermal . Accordingly, isothermal compressibility is defined: where the subscript T indicates that the partial differential is to be taken at constant temperature. Isentropic compressibility is defined: where S is entropy. For a solid, the distinction between the two is usually negligible. Since the density ρ of

2296-441: The design of aircraft. These effects, often several of them at a time, made it very difficult for World War II era aircraft to reach speeds much beyond 800 km/h (500 mph). Many effects are often mentioned in conjunction with the term "compressibility", but regularly have little to do with the compressible nature of air. From a strictly aerodynamic point of view, the term should refer only to those side-effects arising as

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2352-1159: The evolution, function, allostery and folding of protein compexes. 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. Main methods to study protein–ligand interactions are principal hydrodynamic and calorimetric techniques, and principal spectroscopic and structural methods such as 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 , 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 . For example,

2408-408: The isentropic compressibility can be expressed as: The inverse of the compressibility is called the bulk modulus , often denoted K (sometimes B or β {\displaystyle \beta } ).). The compressibility equation relates the isothermal compressibility (and indirectly the pressure) to the structure of the liquid. The isothermal compressibility is generally related to

2464-505: 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 forces , such as ionic bonds , hydrogen bonds and Van der Waals forces . The association or docking is actually reversible through dissociation . Measurably irreversible covalent bonding between

2520-468: The liquid or gas from the voids. This can happen over a period of time, resulting in settlement . It is an important concept in geotechnical engineering in the design of certain structural foundations. For example, the construction of high-rise structures over underlying layers of highly compressible bay mud poses a considerable design constraint, and often leads to use of driven piles or other innovative techniques. The degree of compressibility of

2576-426: The lungs.) This form of bubble contrast medium is generated on an ad hoc basis by the testing clinician by agitating normal saline (e.g., by rapidly and repeatedly transferring the saline between two connected syringes) immediately prior to injection. There are a variety of microbubble contrast agents. Microbubbles differ in their shell makeup, gas core makeup, and whether or not they are targeted. Regardless of

2632-417: 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

2688-1124: 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 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. Ligands of proteins can be characterized also by

2744-442: The overall potency of a drug or a naturally produced (biosynthesized) hormone. 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 , antagonist , or inverse agonist , depending on

2800-462: 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

2856-444: 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 of the agonist that is required to produce the physiological response (often measured as EC 50 , the concentration required to produce the half-maximal response). High-affinity ligand binding implies that

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2912-401: 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 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

2968-457: The physiological response produced. 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 , 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. For hydrophobic ligands (e.g. PIP2) in complex with

3024-583: The shell or gas core composition, microbubble size is fairly uniform. They lie within a range of 1–4 micrometres in diameter. That makes them smaller than red blood cells , which allows them to flow easily through the circulation as well as the microcirculation. Targeted microbubbles are under preclinical development. They retain the same general features as untargeted microbubbles, but they are outfitted with ligands that bind specific receptors expressed by cell types of interest, such as inflamed cells or cancer cells. Current microbubbles in development are composed of

3080-454: The strong echogenicity into a contrast-enhanced image of the area of interest. In this way, the bloodstream's echo is enhanced, thus allowing the clinician to distinguish blood from surrounding tissues. Targeted contrast-enhanced ultrasound works in a similar fashion, with a few alterations. Microbubbles targeted with ligands that bind certain molecular markers that are expressed by the area of imaging interest are still injected systemically in

3136-448: The target cell type. Since the antibodies are not humanized, they will elicit an immune response when used in human therapy. Humanizing antibodies is an expensive and time-intensive process, so it would be ideal to find an alternative source of ligands, such as synthetically manufactured targeting peptides that perform the same function, but without the immune issues. There are two forms of contrast-enhanced ultrasound, untargeted (used in

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