1.
Drug
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A drug is any substance that, when inhaled, injected, smoked, consumed, absorbed via a patch on the skin, or dissolved under the tongue, causes a physiological change in the body. In pharmacology, a drug, also called a medication or medicine, is a chemical substance used to treat, cure, prevent. Traditionally drugs were obtained through extraction from plants, but more recently also by organic synthesis. Pharmaceutical drugs may be used for a duration, or on a regular basis for chronic disorders. Another major classification system is the Biopharmaceutics Classification System and this classifies drugs according to their solubility and permeability or absorption properties. Psychoactive drugs are chemical substances that affect the function of the nervous system, altering perception. They include alcohol, a depressant, and the nicotine and caffeine. These three are the most widely consumed psychoactive drugs worldwide and are also considered recreational drugs since they are used for rather than medicinal purposes. Other recreational drugs include hallucinogens, opiates and amphetamines and some of these are used in spiritual or religious settings. Some drugs can cause addiction and all drugs can have side effects, excessive use of stimulants can promote stimulant psychosis. Many recreational drugs are illicit and international such as the Single Convention on Narcotic Drugs exist for the purpose of their prohibition. The transitive verb to drug arose later and invokes the psychoactive rather than properties of a substance. A medication or medicine is a drug taken to cure or ameliorate any symptoms of an illness or medical condition, the use may also be as preventive medicine that has future benefits but does not treat any existing or pre-existing diseases or symptoms. In the United Kingdom, behind-the-counter medicines are called pharmacy medicines which can only be sold in registered pharmacies and these medications are designated by the letter P on the label. The range of medicines available without a prescription varies from country to country, medications are typically produced by pharmaceutical companies and are often patented to give the developer exclusive rights to produce them. Those that are not patented are called generic drugs since they can be produced by other companies without restrictions or licenses from the patent holder, pharmaceutical drugs are usually categorised into drug classes. A group of drugs will share a chemical structure, or have the same mechanism of action. Another major classification system is the Biopharmaceutics Classification System and this groups drugs according to their solubility and permeability or absorption properties
2.
Jmol
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Jmol is computer software for molecular modelling chemical structures in 3-dimensions. Jmol returns a 3D representation of a molecule that may be used as a teaching tool and it is written in the programming language Java, so it can run on the operating systems Windows, macOS, Linux, and Unix, if Java is installed. It is free and open-source software released under a GNU Lesser General Public License version 2.0, a standalone application and a software development kit exist that can be integrated into other Java applications, such as Bioclipse and Taverna. A popular feature is an applet that can be integrated into web pages to display molecules in a variety of ways, for example, molecules can be displayed as ball-and-stick models, space-filling models, ribbon diagrams, etc. Jmol supports a range of chemical file formats, including Protein Data Bank, Crystallographic Information File, MDL Molfile. There is also a JavaScript-only version, JSmol, that can be used on computers with no Java, the Jmol applet, among other abilities, offers an alternative to the Chime plug-in, which is no longer under active development. While Jmol has many features that Chime lacks, it does not claim to reproduce all Chime functions, most notably, Chime requires plug-in installation and Internet Explorer 6.0 or Firefox 2.0 on Microsoft Windows, or Netscape Communicator 4.8 on Mac OS9. Jmol requires Java installation and operates on a variety of platforms. For example, Jmol is fully functional in Mozilla Firefox, Internet Explorer, Opera, Google Chrome, fast and Scriptable Molecular Graphics in Web Browsers without Java3D
3.
5-HT3 receptor
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This ion channel is cation-selective and mediates neuronal depolarization and excitation within the central and peripheral nervous systems. As with other ligand gated ion channels, the 5-HT3 receptor consists of five subunits arranged around a central ion conducting pore, which is permeable to sodium, potassium, and calcium ions. Binding of the neurotransmitter 5-hydroxytryptamine to the 5-HT3 receptor opens the channel, the rapidly activating, desensitizing, inward current is predominantly carried by sodium and potassium ions. 5-HT3 receptors have a negligible permeability to anions and they are most closely related by homology to the nicotinic acetylcholine receptor. The 5-HT3 receptor differs markedly in structure and mechanism from the other 5-HT receptor subtypes, a functional channel may be composed of five identical 5-HT3A subunits or a mixture of 5-HT3A and one of the other four 5-HT3B, 5-HT3C, 5-HT3D, or 5-HT3E subunits. It appears that only the 5-HT3A subunits form functional homopentameric channels, all other subunit subtypes must heteropentamerize with 5-HT3A subunits to form functional channels. Additionally, there has not currently been any pharmacological difference found between the heteromeric 5-HT3AC, 5-HT3AD, 5-HT3AE, and the homomeric 5-HT3A receptor, the subunits surround a central ion channel in a pseudo-symmetric manner. The 5-HT3 receptor gene is located on human chromosomal region 11q23. 1-q23.2 and it is similar in structure to the mouse gene which has 9 exons and is spread over ~13 kb. Interestingly, four of its introns are exactly in the position as the introns in the homologous α7-Acetylcholine receptor gene. Genes that code for the subunits of the 5-HT3 receptor have been identified, HTR3A and HTR3B for the 5-HT3A and 5-HT3B subunits and in addition HTR3C, HTR3D and HTR3E genes encoding 5-HT3C, 5-HT3D and 5-HT3E subunits. The latter three tend to show peripherally restricted pattern of expression, with levels in the gut. In human duodenum and stomach, for example, 5-HT3C and 5-HT3E mRNA might be greater than for 5-HT3A, there is some evidence to suggest that the 5-HT3 receptor subunits are an important contribution to the effectiveness of these compounds. In patients treated with drugs, certain polymorphism of the HTR3B gene could predict successful antiemetic treatment. This could indicate that the 5-HT3B receptor subunit could be used as biomarker of drug efficacy. HTR3C and HTR3E do not seem to form functional homomeric channels, the pathophysiological role for these additional subunits has yet to be identified. The 5-HT3 receptor is expressed throughout the central and peripheral nervous systems, 5-HT3 receptors are also present on presynaptic nerve terminals. There is some evidence for a role in modulation of neurotransmitter release, 5-HT1 receptor 5-HT2 receptor 5-HT4 receptor 5-HT5 receptor 5-HT6 receptor 5-HT7 receptor 5-HT3 Receptor at the US National Library of Medicine Medical Subject Headings
4.
5-HT2A receptor
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The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor. This is the main excitatory receptor subtype among the GPCRs for serotonin, although 5-HT2A may also have an effect on certain areas such as the visual cortex. This receptor was first noted for its importance as a target of serotonergic psychedelic drugs such as LSD, later it came back to prominence because it was also found to be mediating, at least partly, the action of many antipsychotic drugs, especially the atypical ones. 5-HT2A may be a receptor for the spread of the human polyoma virus called JC virus. Downregulation of post-synaptic 5-HT2A receptor is an adaptive process provoked by chronic administration of selective serotonin reuptake inhibitors, deceased suicidal and otherwise depressed patients have had more 5-HT2A receptors than normal patients. These findings suggest that post-synaptic 5-HT2A overdensity is involved in the pathogenesis of depression, 5-HT2A is thought to correspond to what was originally described as D subtype of 5-HT receptors by Gaddum and Picarelli. Later it was shown that the 5-HT2 was very close to 5-HT1C and thus were clubbed together, thus the 5-HT2 receptor family is composed of three separate molecular entities, the 5-HT2A, the 5-HT2B and the 5-HT2C receptors. 5-HT2A is expressed throughout the central nervous system. It is expressed near most of the serotoninergic terminal rich areas, including neocortex, in the rat cerebellum, the protein has also been found in the Golgi cells of the granular layer, and in the Purkinje cells. In the periphery, it is expressed in platelets and many cell types of the cardiovascular system, in fibroblasts. Additionally, 5-HT2A mRNA expression has been observed in human monocytes, the 5-HT2A receptor is known primarily to couple to the Gαq signal transduction pathway. Upon receptor stimulation with agonist, Gαq and β-γ subunits dissociate to initiate downstream effector pathways, Gαq stimulates phospholipase C activity, which subsequently promotes the release of diacylglycerol and inositol triphosphate, which in turn stimulate protein kinase C activity and Ca2+ release. Other 5-HT2A agonists like LSD also have potent anti-inflammatory effects against TNF-alpha-induced inflammation, activation of the 5-HT2A receptor in hypothalamus causes increases in hormonal levels of oxytocin, prolactin, ACTH, corticosterone, and renin. A very large family of derivatives from these three classes has been developed, and their structure-activity relationships have been extensively researched, agonists acting at 5-HT2A receptors located on the apical dendrites of pyramidal cells within regions of the prefrontal cortex are believed to mediate hallucinogenic activity. Newer findings reveal that psychoactive effects of classic psychedelics are mediated by the receptor heterodimer 5-HT2A–mGlu2, agonists enhance dopamine in PFC, enhances memory and plays an active role in attention and learning. O-4310, 5-HT2A selective, claimed to have 100x selectivity over 5-HT2C and be inactive at 5-HT2B PHA-57378, dual 5-HT2A / 5-HT2C agonist, anxiolytic effects in animal studies. 25C-NBOMe Methysergide, a congener of methylergonovine, used in treatment of migraine blocks 5-HT2A and 5-HT2C receptors, oSU-6162 acts as a partial agonist at both 5-HT2A and dopamine D2 receptors 25CN-NBOH, 100x selectivity for 5-HT2A over 5-HT2C, 46x selectivity over 5-HT2B. Efavirenz, a drug, produces psychiatric side effects thought to be mediated by 5-HT2A
5.
Serotonin transporter
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The serotonin transporter also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of transporter protein that transports serotonin from the synaptic cleft to the presynaptic neuron. This transport of serotonin by the SERT protein terminates the action of serotonin and this protein is the target of many antidepressant medications of the SSRI and Tricyclic antidepressant classes. It is a member of the sodium, neurotransmitter symporter family, serotonin-Reuptake transporters are dependent on both the concentration of potassium ion in the cytoplasm and the concentrations of sodium and chloride ions in the extracellular fluid. In order to function properly the Serotonin Transporter requires the potential created by the sodium-potassium adenosine triphosphatase. Right after the release of the Serotonin in the cytoplasm a potassium ion binds to the transporter which is now able to back out returning to its active state. The serotonin transporter removes serotonin from the synaptic cleft back into the synaptic boutons, thus, it terminates the effects of serotonin and simultaneously enables its reuse by the presynaptic neuron. Neurons communicate by using chemical messengers like serotonin between cells, the transporter protein, by recycling serotonin, regulates its concentration in a gap, or synapse, and thus its effects on a receiving neuron’s receptors. The serotonin transporter is also present in platelets, there, serotonin functions as a vasoconstrictive substance and it also serves as a signalling molecule to induce platelet aggregation. SERT spans the plasma membrane 12 times and it belongs to NE, DA, SERT monoamine transporter family. Transporters are important sites for agents that treat psychiatric disorders, drugs that reduce the binding of serotonin to transporters are used to treat mental disorders. The SSRI Fluoxetine and the Tricyclic antidepressant Clomipramine are examples of serotonin reuptake inhibitors, however, studies on SERT showed that tricyclic antidepressants and selective serotonin reuptake inhbitors bind to the central binding site overlapping the substrate binding site. Isosteres 3-cis-indole 8a, Ki =220 pM The gene that encodes the serotonin transporter is called solute carrier family 6, in humans the gene is found on chromosome 17 on location 17q11. 1–q12. These phenotypic changes may, e. g. be increased anxiety, the short variation has 14 repeats of a sequence while the long variation has 16 repeats. The short variation leads to less transcription for SLC6A4, and it has found that it can partly account for anxiety-related personality traits. This polymorphism has been investigated in over 300 scientific studies. The 5-HTTLPR polymorphism may be subdivided further, One study published in 2000 found 14 allelic variants in a group of around 200 Japanese and Caucasian people. In addition to altering the expression of SERT protein and concentrations of serotonin in the brain
6.
Regulation of therapeutic goods
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The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the level by a single agency. In other jurisdictions they are regulated at the level, or at both state and national levels by various bodies, as is the case in Australia. The role of therapeutic goods regulation is designed mainly to protect the health, regulation is aimed at ensuring the safety, quality, and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered before they are allowed to be marketed, there is usually some degree of restriction of the availability of certain therapeutic goods depending on their risk to consumers. Therapeutic goods in Australia are regulated by the Therapeutic Goods Administration, there are 5 main categories, Normal Medicines - Cough, cold and fever medicines, antiseptics, vitamins and others. Sold freely in pharmacies and some large supermarkets, red Stripe Medicines - These medicines are sold only with medical prescription. Antibiotics, Anti allergenics, Anti inflammatories, and other medicines, in Brazil, governmental control is loose on this type, it is not uncommon to buy this type of prescription medicine over the counter without a prescription. Red Stripe Psychoactive Medicines - These medicines are only with a Special Control white medical prescription with carbon copy. The original must be retained by the pharmacist after the sale, Drugs include anti-depressants, anti-convulsants, some sleep aids, anti-psychotics and other non-habit-inducing controlled medicines. Though some consider them habit inducing, anabolic steroids are also regulated under this category, black Stripe Medicines - These medicines are sold only with the Blue B Form medical prescription, which is valid for 30 days and must be retained by the pharmacist after the sale. Includes sedatives, some anorexic inducers and other habit-inducing controlled medicines, includes amphetamines and other stimulants, opioids and other strong habit-forming controlled medicines. In Canada, regulation of goods are governed by the Food and Drug Act. In addition, the Controlled Drugs and Substances Act requires additional regulatory requirements for controlled drugs, the regulation of drugs in Burma is governed by the Food and Drug Administration and Food and Drug Board of Authority. The regulation of drugs in China is governed by the China Food, Medicines for Human Use in the United Kingdom are regulated by the Medicines and Healthcare products Regulatory Agency. The availability of drugs is regulated by classification by the MHRA as part of marketing authorisation of a product, Medicines in the Republic of Ireland are regulated according to the Misuse of Drugs Regulations 1988. Controlled drugs are divided into five categories based on their potential for misuse, cD1, cannabis, lysergamide, coca leaf, etc. Use prohibited except in limited circumstances where a license has been granted, CD2, amphetamine, methadone, morphine, fentanyl, oxycodone, tapentadol, etc
7.
Ligand (biochemistry)
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In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. 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 conformation of the target protein. In DNA-ligand binding studies, the ligand can be a molecule, ion. 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 constant is usually a very small number. Binding occurs by intermolecular forces, such as bonds, hydrogen bonds. The association of 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 metalorganic and inorganic chemistry, in biochemistry it is whether the ligand generally binds at a metal site. In general, the interpretation of ligand is contextual with regards to what sort of binding has been observed, the etymology stems from ligare, which means to bind. Ligand binding to a receptor protein alters the chemical conformation by affecting the shape orientation. The conformation of a receptor protein composes the functional state, ligands include substrates, inhibitors, activators, 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 a dominant, steric role which drives non-covalent binding in solution. The solvent provides an environment for the ligand and receptor to adapt. Radioligands are radioisotope labeled compounds are used in vivo as tracers in PET studies, the interaction of most ligands with their binding sites can be characterized in terms of a binding affinity. In general, high-affinity binding results in a degree of occupancy for the ligand at its receptor binding site than is the case for low-affinity binding. A ligand that can bind to a receptor, alter the function of the receptor, 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. The lower the Ki concentration is, the more likely there will be a reaction between the pending ion and the receptive antigen. In the example shown to the right, two different ligands bind to the receptor binding site. Only one of the agonists shown can maximally stimulate the receptor and, thus, an agonist that can only partially activate the physiological response is called a partial agonist
8.
Simplified molecular-input line-entry system
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The simplified molecular-input line-entry system is a specification in form of a line notation for describing the structure of chemical species using short ASCII strings. SMILES strings can be imported by most molecule editors for conversion back into two-dimensional drawings or three-dimensional models of the molecules, the original SMILES specification was initiated in the 1980s. It has since modified and extended. In 2007, a standard called OpenSMILES was developed in the open-source chemistry community. Other linear notations include the Wiswesser Line Notation, ROSDAL and SLN, the original SMILES specification was initiated by David Weininger at the USEPA Mid-Continent Ecology Division Laboratory in Duluth in the 1980s. The Environmental Protection Agency funded the project to develop SMILES. It has since modified and extended by others, most notably by Daylight Chemical Information Systems. In 2007, a standard called OpenSMILES was developed by the Blue Obelisk open-source chemistry community. Other linear notations include the Wiswesser Line Notation, ROSDAL and SLN, in July 2006, the IUPAC introduced the InChI as a standard for formula representation. SMILES is generally considered to have the advantage of being slightly more human-readable than InChI, the term SMILES refers to a line notation for encoding molecular structures and specific instances should strictly be called SMILES strings. However, the term SMILES is also used to refer to both a single SMILES string and a number of SMILES strings, the exact meaning is usually apparent from the context. The terms canonical and isomeric can lead to confusion when applied to SMILES. The terms describe different attributes of SMILES strings and are not mutually exclusive, typically, a number of equally valid SMILES strings can be written for a molecule. For example, CCO, OCC and CC all specify the structure of ethanol, algorithms have been developed to generate the same SMILES string for a given molecule, of the many possible strings, these algorithms choose only one of them. This SMILES is unique for each structure, although dependent on the algorithm used to generate it. These algorithms first convert the SMILES to a representation of the molecular structure. A common application of canonical SMILES is indexing and ensuring uniqueness of molecules in a database, there is currently no systematic comparison across commercial software to test if such flaws exist in those packages. SMILES notation allows the specification of configuration at tetrahedral centers, and these are structural features that cannot be specified by connectivity alone and SMILES which encode this information are termed isomeric SMILES
9.
Binding selectivity
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Binding selectivity is defined with respect to the binding of ligands to a substrate forming a complex. A selectivity coefficient is the constant for the reaction of displacement by one ligand of another ligand in a complex with the substrate. Binding selectivity is of importance in biochemistry and in chemical separation processes. The concept of selectivity is used to quantify the extent to which a substrate, A. The simplest case is where the complexes formed have 1,1 stoichiometry, then, the two interactions may be characterized by equilibrium constants KAB and KAC. A + B ↽ − − ⇀ AB, K AB = A + C ↽ − − ⇀ AC, a selectivity coefficient is defined as the ratio of the two equilibrium constants. The greater the selectivity coefficient, the more the ligand C will displace the ligand B from the complex formed with the substrate A, an alternative interpretation is that the greater the selectivity coefficient, the lower the concentration of C that is needed to displace B from AB. Selectivity coefficients are determined experimentally by measuring the two constants, KAB and KAC. In biochemistry the substrate is known as a receptor, a receptor is a protein molecule, embedded in either the plasma membrane or the cytoplasm of a cell, to which one or more specific kinds of signalling molecules may bind. A ligand may be a peptide or another small molecule, such as a neurotransmitter, a hormone, the specificity of a receptor is determined by its spatial geometry and the way it binds to the ligand through non-covalent interactions, such as hydrogen bonding or Van der Waals forces. If a receptor can be isolated a synthetic drug can be developed either to stimulate the receptor, an agonist or to block it, the stomach ulcer drug cimetidine was developed as an H2 antagonist by chemically engineering the molecule for maximum specificity to an isolated tissue containing the receptor. The further use of quantitative structure-activity relationships led to the development of agents such as ranitidine. It is important to note that selectivity when referring to a drug is relative, for example, in a higher dose, a specific drug molecule may also bind to other receptors than those said to be selective. Chelation therapy is a form of treatment in which a chelating ligand is used to selectively remove a metal from the body. Selectivity is determined by various factors and it also forms stronger complexes with oxygen-donor ligands than with nitrogen-donor ligands. Deferoxamine, a naturally occurring siderophore produced by the actinobacter Streptomyces pilosus and was used initially as a chelation therapy agent, synthetic siderophores such as deferiprone and deferasirox have been developed, using the known structure of deferoxamine as a starting point. Chelation occurs with the two oxygen atoms, wilsons disease is caused by a defect in copper metabolism which results in accumulation of copper metal in various organs of the body. The target ion in this case is divalent, Cu2+ and this ion is classified as borderline in the scheme of Ahrland, Chatt and Davies
