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61-424: The affinities (K i ) of MSX-2 for the human adenosine receptors are 5.38 to 14.5   nM for the adenosine A 2A receptor, 2,500   nM for the adenosine A 1 receptor (172- to 465-fold lower than for the A 2A receptor), and >10,000   nM for the adenosine A 2B and A 3 receptors (>690-fold lower than for the A 2A receptor). MSX-2 has poor water solubility , which has limited

122-405: 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,

183-493: 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

244-451: A SiO 2 framework and can be found in a range of marine sediment. Clathrate compounds with formula A 8 B 16 X 30 , where A is an alkaline earth metal , B is a group III element, and X is an element from group IV have been explored for thermoelectric devices. Thermoelectric materials follow a design strategy called the phonon glass electron crystal concept. Low thermal conductivity and high electrical conductivity

305-469: 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

366-698: A class of hosts that form inclusion compounds. A related family of formaldehyde-derived oligomeric rings are pillararenes (pillered arenes). One famous illustration of the stabilizing effect of host-guest complexation is the stabilization of cyclobutadiene by such an organic host. Cyclodextrin (CD) are tubular molecules composed of several glucose units connected by ether bonds. The three kinds of CDs, α-CD (6 units), β-CD (7 units), and γ-CD (8 units) differ in their cavity sizes: 5, 6, and 8 Å, respectively. α-CD can thread onto one PEG chain, while γ-CD can thread onto 2 PEG chains. β-CD can bind with thiophene-based molecule. Cyclodextrins are well established hosts for

427-466: A colorimetric displacement assay is used. Azure A dye is blue when it is unbound, but when it is bound to herapin, it shows a purple color. The binding between Azure A and heparin is weak and reversible. This allows protamine to displace Azure A. Once the dye is liberated it displays a purple color. The degree to which the dye is displaced is proportional to the amount of protamine in the plasma. F-IDA has been used by Kwalczykowski and co-workers to monitor

488-442: A conformationally flexible cavity that allows them to host a variety of guest molecules. These assemblies have shown promise as agents of drug delivery to cancer cells. Encapsulation can control reactivity. For instance, excited state reactivity of free 1-phenyl-3-tolyl-2-proponanone (abbreviated A-CO-B) yields products A-A, B-B, and AB, which result from decarbonylation followed by random recombination of radicals A• and B•. Whereas,

549-478: 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

610-499: 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

671-400: 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

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732-500: 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

793-979: A partly enclosed cavity ( cavitand ). . Cucurbit[n]urils have similar size of γ-CD, which also behave similarly ( e.g. , 1 cucurbit[n]uril can thread onto 2 PEG chains). The structure of cryptophanes contain 6 phenyl rings, mainly connected in 4 ways . Due to the phenyl groups and aliphatic chains, the cages inside cryptophanes are highly hydrophobic, suggesting the capability of capturing non-polar molecules. Based on this, cryptophanes can be employed to capture xenon in aqueous solution, which could be helpful in biological studies. Crown ethers bind cations. Small crown ethers, e.g. 12-crown-4 bind well to small ions such as Li+ and large crowns, such as 24-crown-8 bind better to larger ions. Beyond binding ionic guests, crown ethers also bind to some neutral molecules, e.g. , 1, 2, 3- triazole. Crown ethers can also be threaded with slender linear molecules and/or polymers, giving rise to supramolecular structures called rotaxanes . Given that

854-407: A receptor is incubated with the indicator. When the analyte is added to the mixture, the indicator is released to the environment. Once the indicator is released it either changes color (C-IDA) or fluoresces (F-IDA). IDA offers several advantages versus the traditional ISR chemical sensing approach. First, it does not require the indicator to be covalently bound to the receptor. Secondly, since there

915-423: 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

976-407: 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

1037-491: A system that contains a covalently bound indicator to a receptor though a linker. Once the analyte binds, the indicator changes color or fluoresces. This technique is called the indicator-spacer-receptor approach (ISR). In contrast to ISR, indicator-displacement assay (IDA) utilizes a non-covalent interaction between a receptor (the host), indicator, and an analyte (the guest). Similar to ISR, IDA also utilizes colorimetric (C-IDA) and fluorescence (F-IDA) indicators. In an IDA assay,

1098-504: 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

1159-454: 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

1220-668: 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 . Host%E2%80%93guest chemistry In supramolecular chemistry , host–guest chemistry describes complexes that are composed of two or more molecules or ions that are held together in unique structural relationships by forces other than those of full covalent bonds . Host–guest chemistry encompasses

1281-615: Is desired to produce the Seebeck Effect . When the guest and host framework are appropriately tuned, clathrates can exhibit low thermal conductivity, i.e., phonon glass behavior, while electrical conductivity through the host framework is undisturbed allowing clathrates to exhibit electron crystal . Hofmann clathrates are coordination polymers with the formula Ni(CN) 4 ·Ni(NH 3 ) 2 (arene). These materials crystallize with small aromatic guests (benzene, certain xylenes), and this selectivity has been exploited commercially for

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1342-424: Is no covalent bond, various indicators can be used with the same receptor. Lastly, the media in which the assay may be used is diverse. Chemical sensing techniques such as C-IDA have biological implications. For example, protamine is a coagulant that is routinely administered after cardiopulmonary surgery that counter acts the anti-coagulant activity of herapin. In order to quantify the protamine in plasma samples,

1403-679: Is observed, in other cases, the encapsulated guest cannot escape. An important implication of encapsulation (and host-guest chemistry in general) is that the guest behaves differently from the way it would when in solution. Guest molecules that would react by bimolecular pathways are often stabilized because they cannot combine with other reactants. The spectroscopic signatures of trapped guests are of fundamental interest. Compounds normally highly unstable in solution have been isolated at room temperature when molecularly encapsulated. Examples include cyclobutadiene , arynes or cycloheptatetraene. Large metalla-assemblies, known as metallaprisms , contain

1464-405: 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

1525-442: Is very broad, extending to channels formed between molecules in a crystal lattice in which guest molecules can fit. Inclusion Compound : A complex in which one component (the host) forms a cavity or, in the case of a crystal, a crystal lattice containing spaces in the shape of long tunnels or channels in which molecular entities of a second chemical species (the guest) are located. There is no covalent bonding between guest and host,

1586-479: The Beer–Lambert law . where λ is a wavelength, ℓ {\displaystyle \ell } is the optical path length of the cuvette which contains the solution of the N compounds ( chromophores ), ε i , λ {\displaystyle \varepsilon _{i,\lambda }} is the molar absorbance (also known as the extinction coefficient) of the i th chemical species at

1647-408: The activities of helicase in E.coli . In this study they used thiazole orange as the indicator. The helicase unwinds the dsDNA to make ssDNA. The fluorescence intensity of thiazole orange has a greater affinity for dsDNA than ssDNA and its fluorescence intensity increases when it is bound to dsDNA than when it is unbound. A crystalline solid has been traditionally viewed as a static entity where

1708-478: The analogous terms of host and guest are commonly referred to as enzyme and substrate respectively. Closely related to host–guest chemistry, are inclusion compounds (also known as an inclusion complexes ). Here, a chemical complex in which one chemical compound (the "host") has a cavity into which a "guest" compound can be accommodated. The interaction between the host and guest involves purely van der Waals bonding . The definition of inclusion compounds

1769-493: The attraction being generally due to van der Waals forces. Yet another related class of compounds are clathrates , which often consisting of a lattice that traps or contains molecules. The word clathrate is derived from the Latin clathratus ( clatratus ), meaning 'with bars, latticed '. Molecular encapsulation concerns the confinement of a guest within a larger host. In some cases, true host-guest reversibility

1830-399: The capacity to produce pro-motivational effects. MSX-2 and MSX-3 were first described in the scientific literature by 1998. Subsequently, MSX-4 was developed and described by 2008. This pharmacology -related article is a stub . You can help Misplaced Pages by expanding it . Affinity (pharmacology) In biochemistry and pharmacology , a ligand is a substance that forms

1891-643: The crown ethers are not bound to the chains, they can move up and down the threading molecule. Crown ether complexes of metal cations (and the corresponding complexes of Cryptands ) are not considered to be inclusion complexes since the guest is bound by forces stronger than van der Waals bonding. Zeolites have open framework structures with cavities in which guest species can reside. Aluminosilicates being their composition, zeolites are rigid. Many structures are known, some of which are considerably useful as catalysts and for separations. Silica clathrasil are compounds structurally similar to clathrate hydrates with

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1952-451: The emission of phosphorescence. Another technique for evaluating host-guest interactions is calorimetry . Host guest complexation is pervasive in biochemistry. Many protein hosts recognize and hence selectively bind other biomolecules. When the protein host is an enzyme, the guests are called substrates. While these concepts are well established in biological systems, the applications of synthetic host-guest chemistry remains mostly in

2013-1159: 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,

2074-416: The fluorescnece emission differences between the complex and the cages, the information could be encrypted. Although some host-guest interactions are not strong, increasing the amount of the host-guest interaction can improve the mechanical properties of the materials. As an example, threading the host molecules onto the polymer is one of the commonly used strategies for increasing the mechanical properties of

2135-413: The formation of inclusion compounds. Illustrative is the case of ferrocene which is inserted into the cyclodextrin at 100 °C under hydrothermal conditions. Cucurbiturils are macrocyclic molecules made of glycoluril ( =C 4 H 2 N 4 O 2 = ) monomers linked by methylene bridges ( −CH 2 − ). The oxygen atoms are located along the edges of the band and are tilted inwards, forming

2196-406: The fragrance lasts much longer due to the slow-release action. Photolytically-sensitive caged compounds have been examined as containers for releasing a drug or reagent . An encryption system constructed by pillar[5]arene, spiropyran and pentanenitrile (free state and grafted to polymer) was constructed by Wang et al . After UV irradiation, spiropyran would transform into merocyanine. When

2257-476: The host and guest molecules combine to form a single complex, the equilibrium is represented as and the equilibrium constant, K, is defined as where [X] denotes the concentration of a chemical species X (all activity coefficients are assumed to have a numerical values of 1). The mass-balance equations, at any data point, where T G {\displaystyle T_{G}} and T H {\displaystyle T_{H}} represent

2318-658: The idea of molecular recognition and interactions through non-covalent bonding . Non-covalent bonding is critical in maintaining the 3D structure of large molecules, such as proteins and is involved in many biological processes in which large molecules bind specifically but transiently to one another. Although non-covalent interactions could be roughly divided into those with more electrostatic or dispersive contributions, there are few commonly mentioned types of non-covalent interactions: ionic bonding , hydrogen bonding , van der Waals forces and hydrophobic interactions . Host-guest interaction has raised dramatical attention since it

2379-410: The interaction might vary, such as hydrophobic effect and van der Waals forces Binding between host and guest can be highly selective, in which case the interaction is called molecular recognition . Often, a dynamic equilibrium exist between the unbound and the bound states: The "host" component is often the larger molecule, and it encloses the smaller, "guest", molecule. In biological systems,

2440-408: The lifetime of phosphoresce. In this circumstance, α-CD and CB could be used, in which the phosphor is served as a guest to interact with the host. For example, 4-phenylpyridium derivatives interacted with CB, and copolymerize with acrylamide . The resulting polymer yielded ~2 s of phosphorescence lifetime. Additionally, Zhu et al used crown ether and potassium ion to modify the polymer, and enhance

2501-505: 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

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2562-583: The movements of its atomic components are limited to its vibrational equilibrium. As seen by the transformation of graphite to diamond, solid to solid transformation can occur under physical or chemical pressure. It has been proposed that the transformation from one crystal arrangement to another occurs in a cooperative manner. Most of these studies have been focused in studying an organic or metal-organic framework. In addition to studies of macromolecular crystalline transformation, there are also studies of single-crystal molecules that can change their conformation in

2623-417: 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

2684-470: The observed chemical shift value, δ , arising from a given atom contained in a reagent molecule and one or more complexes of that reagent, will be the concentration-weighted average of all shifts of those chemical species. Chemical exchange is assumed to be rapid on the NMR time-scale. Using UV-vis spectroscopy, the absorbance of each species is proportional to the concentration of that species, according to

2745-1124: 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

2806-442: 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

2867-462: 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

2928-444: 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

2989-401: 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

3050-457: 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

3111-524: The polymer. It takes time for the host molecules to de-thread from the polymer, which can be a way of energy dissipation. Another method is to use the slow exchange host-guest interaction. Though the slow exchange improves the mechanical properties, simultaneously, self-healing properties will be sacrificed. Silicon surfaces functionalized with tetraphosphonate cavitands have been used to singularly detect sarcosine in water and urine solutions. Traditionally, chemical sensing has been approached with

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3172-436: The presence of organic solvents. An organometallic complex has been shown to morph into various orientations depending on whether it is exposed to solvent vapors or not. Host guest systems have been proposed to remove hazardous materials. Certain calix[4]arenes bind cesium-137 ions, which could in principle be applied to clean up radioactive wastes. Some receptors binds carcinogens. According to food chemist Udo Pollmer of

3233-462: The quantity observed X i o b s {\displaystyle X_{i}^{obs}} . Then, a sum of squares, U, over all data points, np, can be defined as and this can be minimized with respect to the stability constant value, K, and a parameter such the chemical shift of the species HG (nmr data) or its molar absorbency (uv/vis data). This procedure is applicable to 1:1 adducts. With nuclear magnetic resonance (NMR) spectra

3294-559: The realm of aspiration. One major exception, being zeolites where host-guest chemistry is their raison d'etre. A self-healing hydrogel constructed from modified cyclodextrin and adamantane . Another strategy is to use the interaction between the polymer backbone and host molecule (host molecule threading onto the polymer). If the threading process is fast enough, self-healing can also be achieved. Cyclodextrin forms inclusion compounds with fragrances which are more stable towards exposure to light and air. When incorporated into textiles

3355-448: The same substrate upon encapsulation reacts to yield the controlled recombination product A-B, and rearranged products (isomers of A-CO-B). Organic hosts are occasionally called cavitands . The original definition proposed by Cram includes many classes of molecules: cyclodextrins , calixarenes , pillararenes and cucurbiturils . Calixarenes and related formaldehyde-arene condensates ( resorcinarenes and pyrogallolarenes ) form

3416-593: The separation of these hydrocarbons. Metal organic frameworks (MOFs) form clathrates. Urea , a small molecule with the formula O=C(NH 2 ) 2 , has the peculiar property of crystallizing in open but rigid networks. The cost of efficient molecular packing is compensated by hydroge-bonding. Ribbons of hydrogen-bonded urea molecules form tunnel-like host into which many organic guests bind. Urea-clathrates have been well investigated for separations. Beyond urea, several other organic molecules form clathrates: [[[thiourea]], hydroquinone , and Dianin's compound . When

3477-402: The total concentrations, of host and guest, can be reduced to a single quadratic equation in, say, [G] and so can be solved analytically for any given value of K. The concentrations [H] and [HG] can then derived. The next step in the calculation is to calculate the value, X i c a l c {\displaystyle X_{i}^{calc}} , of a quantity corresponding to

3538-406: The use of MSX-2 itself. Water-soluble ester prodrugs of MSX-2, including MSX-3 (a phosphate ester prodrug) and MSX-4 (an amino acid ester prodrug), have been developed and used in place of MSX-2. MSX-3 is best-suited for use by intravenous administration , whereas MSX-4 can be administered by oral administration . MSX-3 and MSX-4 reverse motivational deficits in animals and hence have

3599-451: The visible light was shined on the material, the merocyanine close to the pillar[5]arene-free pentanenitrile complex had faster transformation to spiropyran; on the contrary, the one close to pillar[5]arene-grafted pentanenitrile complex has much slower transformation rate. This spiropyran-merocyanine transformation can be used for message encryption. Another strategy is based on the metallacages and polycyclic aromatic hydrocarbons. Because of

3660-572: The wavelength λ, c i is its concentration. When the concentrations have been calculated as above and absorbance has been measured for samples with various concentrations of host and guest, the Beer–Lambert law provides a set of equations, at a given wavelength, that which can be solved by a linear least-squares process for the unknown extinction coefficient values at that wavelength. Host-guest structures can be probed by their luminescence. A rigid matrix protects emitters from being quenched, extending

3721-426: Was discovered. It is an important field, because many biological processes require the host-guest interaction, and it can be useful in some material designs. There are several typical host molecules, such as, cyclodextrin, crown ether, et al . "Host molecules" usually have "pore-like" structure that is able to capture a "guest molecules". Although called molecules, hosts and guests are often ions. The driving forces of

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