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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 molecule which exerts a biochemical or physiological effect on the cell, tissue, organ, or organism. It is the science of drugs including their origin, composition, pharmacokinetics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function. If substances have medicinal properties, they are considered pharmaceuticals.
In biochemistry, allosteric regulation is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site.
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 agonist, while an inverse agonist causes an action opposite to that of the agonist.
In biochemistry and pharmacology, receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems. These signals are typically chemical messengers which bind to a receptor and cause some form of cellular/tissue response, e.g. a change in the electrical activity of a cell. There are three main ways the action of the receptor can be classified: relay of signal, amplification, or integration. Relaying sends the signal onward, amplification increases the effect of a single ligand, and integration allows the signal to be incorporated into another biochemical pathway.
In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered.
Drug design, often referred to as rational drug design or simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic small molecule that activates or inhibits the function of a biomolecule such as a protein, which in turn results in a therapeutic benefit to the patient. In the most basic sense, drug design involves the design of molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it. Drug design frequently but not necessarily relies on computer modeling techniques. This type of modeling is sometimes referred to as computer-aided drug design. Finally, drug design that relies on the knowledge of the three-dimensional structure of the biomolecular target is known as structure-based drug design. In addition to small molecules, biopharmaceuticals including peptides and especially therapeutic antibodies are an increasingly important class of drugs and computational methods for improving the affinity, selectivity, and stability of these protein-based therapeutics have also been developed.
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of receptor proteins. They are sometimes called blockers; examples include alpha blockers, beta blockers, and calcium channel blockers. In pharmacology, antagonists have affinity but no efficacy for their cognate receptors, and binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active site or to the allosteric site on a receptor, or they may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex, which, in turn, depends on the nature of antagonist–receptor binding. The majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptors.
Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs. The effects can include those manifested within animals, microorganisms, or combinations of organisms.
Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors (SSTRs). Opioid receptors are distributed widely in the brain, in the spinal cord, on peripheral neurons, and digestive tract.
Agmatine, also known as 4-aminobutyl-guanidine, was discovered in 1910 by Albrecht Kossel. It is a chemical substance which is naturally created from the amino acid arginine. Agmatine has been shown to exert modulatory action at multiple molecular targets, notably: neurotransmitter systems, ion channels, nitric oxide (NO) synthesis and polyamine metabolism and this provides bases for further research into potential applications.
Neuropharmacology is the study of how drugs affect function in the nervous system, and the neural mechanisms through which they influence behavior. There are two main branches of neuropharmacology: behavioral and molecular. Behavioral neuropharmacology focuses on the study of how drugs affect human behavior (neuropsychopharmacology), including the study of how drug dependence and addiction affect the human brain. Molecular neuropharmacology involves the study of neurons and their neurochemical interactions, with the overall goal of developing drugs that have beneficial effects on neurological function. Both of these fields are closely connected, since both are concerned with the interactions of neurotransmitters, neuropeptides, neurohormones, neuromodulators, enzymes, second messengers, co-transporters, ion channels, and receptor proteins in the central and peripheral nervous systems. Studying these interactions, researchers are developing drugs to treat many different neurological disorders, including pain, neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, psychological disorders, addiction, and many others.
In biochemistry and pharmacology, 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 on a target protein. 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.
In biochemistry, an orphan receptor is a protein that has a similar structure to other identified receptors but whose endogenous ligand has not yet been identified. If a ligand for an orphan receptor is later discovered, the receptor is referred to as an "adopted orphan". Conversely, the term orphan ligand refers to a biological ligand whose cognate receptor has not yet been identified.
In biology, cell signaling or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellular life in prokaryotes and eukaryotes. Signals that originate from outside a cell can be physical agents like mechanical pressure, voltage, temperature, light, or chemical signals. Cell signaling can occur over short or long distances, and as a result can be classified as autocrine, juxtacrine, intracrine, paracrine, or endocrine. Signaling molecules can be synthesized from various biosynthetic pathways and released through passive or active transports, or even from cell damage.
In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targets to which the drug binds, such as an enzyme or receptor. Receptor sites have specific affinities for drugs based on the chemical structure of the drug, as well as the specific action that occurs there.
Chemogenomics, or chemical genomics, is the systematic screening of targeted chemical libraries of small molecules against individual drug target families with the ultimate goal of identification of novel drugs and drug targets. Typically some members of a target library have been well characterized where both the function has been determined and compounds that modulate the function of those targets have been identified. Other members of the target family may have unknown function with no known ligands and hence are classified as orphan receptors. By identifying screening hits that modulate the activity of the less well characterized members of the target family, the function of these novel targets can be elucidated. Furthermore, the hits for these targets can be used as a starting point for drug discovery. The completion of the human genome project has provided an abundance of potential targets for therapeutic intervention. Chemogenomics strives to study the intersection of all possible drugs on all of these potential targets.
Endomorphins are considered to be natural opioid neurotransmitters central to pain relief. The two known endomorphins, endomorphin-1 and endomorphin-2, are tetrapeptides, consisting of Tyr-Pro-Trp-Phe and Tyr-Pro-Phe-Phe amino acid sequences respectively. These sequences fold into tertiary structures with high specificity and affinity for the μ-opioid receptor, binding it exclusively and strongly. Bound μ-opioid receptors typically induce inhibitory effects on neuronal activity. Endomorphin-like immunoreactivity exists within the central and peripheral nervous systems, where endomorphin-1 appears to be concentrated in the brain and upper brainstem, and endomorphin-2 in the spinal cord and lower brainstem. Because endomorphins activate the μ-opioid receptor, which is the target receptor of morphine and its derivatives, endomorphins possess significant potential as analgesics with reduced side effects and risk of addiction.
Molecular binding is an attractive interaction between two molecules that results in a stable association in which the molecules are in close proximity to each other. It is formed when atoms or molecules bind together by sharing of electrons. It often, but not always, involves some chemical bonding.
Receptor theory is the application of receptor models to explain drug behavior. Pharmacological receptor models preceded accurate knowledge of receptors by many years. John Newport Langley and Paul Ehrlich introduced the concept of a receptor that would mediate drug action at the beginning of the 20th century. Alfred Joseph Clark was the first to quantify drug-induced biological responses. So far, nearly all of the quantitative theoretical modelling of receptor function has centred on ligand-gated ion channels and GPCRs.
Chemoproteomics entails a broad array of techniques used to identify and interrogate protein-small molecule interactions. Chemoproteomics complements phenotypic drug discovery, a paradigm that aims to discover lead compounds on the basis of alleviating a disease phenotype, as opposed to target-based drug discovery, in which lead compounds are designed to interact with predetermined disease-driving biological targets. As phenotypic drug discovery assays do not provide confirmation of a compound's mechanism of action, chemoproteomics provides valuable follow-up strategies to narrow down potential targets and eventually validate a molecule's mechanism of action. Chemoproteomics also attempts to address the inherent challenge of drug promiscuity in small molecule drug discovery by analyzing protein-small molecule interactions on a proteome-wide scale. A major goal of chemoproteomics is to characterize the interactome of drug candidates to gain insight into mechanisms of off-target toxicity and polypharmacology.
References
- ↑ Raffa RB, Porreca F (1989). "Thermodynamic analysis of the drug-receptor interaction". Life Sciences. 44 (4): 245–58. doi:10.1016/0024-3205(89)90182-3. PMID 2536880.
- ↑ Moy VT, Florin EL, Gaub HE (October 1994). "Intermolecular forces and energies between ligands and receptors". Science. 266 (5183): 257–9. Bibcode:1994Sci...266..257M. doi:10.1126/science.7939660. PMID 7939660.
- ↑ Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G (2012). "Chapter 3: How drugs act: molecular aspects". Rang and Dale's Pharmacology. Edinburgh; New York: Elsevier/Churchill Livingstone. pp. 20–48. ISBN 978-0-7020-3471-8.
- ↑ Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G (2012). "Chapter 2: How drugs act: general principles". Rang and Dale's Pharmacology. Edinburgh; New York: Elsevier/Churchill Livingstone. pp. 6–19. ISBN 978-0-7020-3471-8.
- ↑ Overington JP, Al-Lazikani B, Hopkins AL (December 2006). "How many drug targets are there?". Nature Reviews. Drug Discovery. 5 (12): 993–6. doi:10.1038/nrd2199. PMID 17139284. S2CID 11979420.
- ↑ Landry Y, Gies JP (February 2008). "Drugs and their molecular targets: an updated overview". Fundamental & Clinical Pharmacology. 22 (1): 1–18. doi:10.1111/j.1472-8206.2007.00548.x. PMID 18251718. S2CID 205630866.
- ↑ Lundstrom K (2009). "An overview on GPCRs and drug discovery: structure-based drug design and structural biology on GPCRs". G Protein-Coupled Receptors in Drug Discovery. Methods in Molecular Biology. Vol. 552. pp. 51–66. doi:10.1007/978-1-60327-317-6_4. ISBN 978-1-60327-316-9. PMC 7122359 . PMID 19513641.
- ↑ Dixon SJ, Stockwell BR (December 2009). "Identifying druggable disease-modifying gene products". Current Opinion in Chemical Biology. 13 (5–6): 549–55. doi:10.1016/j.cbpa.2009.08.003. PMC 2787993 . PMID 19740696.
- ↑ Moffat JG, Vincent F, Lee JA, Eder J, Prunotto M (2017). "Opportunities and challenges in phenotypic drug discovery: an industry perspective". Nature Reviews. Drug Discovery. 16 (8): 531–543. doi: 10.1038/nrd.2017.111 . PMID 28685762. S2CID 6180139.
Novelty of target and MoA [Mechanism of Action] is the second major potential advantage of PDD [Phenotypic Drug Discovery]. In addition to identifying novel targets, PDD can contribute to improvements over existing therapies by identifying novel physiology for a known target, exploring 'undrugged' targets that belong to well known drug target classes or discovering novel MoAs, including new ways of interfering with difficult-to-drug targets.
- ↑ Lee H, Lee JW (2016). "Target identification for biologically active small molecules using chemical biology approaches". Archives of Pharmacal Research. 39 (9): 1193–201. doi:10.1007/s12272-016-0791-z. PMID 27387321. S2CID 13577563.
- ↑ Lomenick B, Olsen RW, Huang J (January 2011). "Identification of direct protein targets of small molecules". ACS Chemical Biology. 6 (1): 34–46. doi:10.1021/cb100294v. PMC 3031183 . PMID 21077692.
- ↑ Jung HJ, Kwon HJ (2015). "Target deconvolution of bioactive small molecules: the heart of chemical biology and drug discovery". Archives of Pharmacal Research. 38 (9): 1627–41. doi:10.1007/s12272-015-0618-3. PMID 26040984. S2CID 2399601.
- 1 2 Gunnarsson L, Jauhiainen A, Kristiansson E, Nerman O, Larsson DG (August 2008). "Evolutionary conservation of human drug targets in organisms used for environmental risk assessments". Environmental Science & Technology. 42 (15): 5807–5813. Bibcode:2008EnST...42.5807G. doi:10.1021/es8005173. PMID 18754513.
- ↑ Larsson DG, Adolfsson-Erici M, Parkkonen J, Pettersson M, Berg AM, Olsson PE, Förlin L (April 1999). "Ethinyloestradiol — an undesired fish contraceptive?". Aquatic Toxicology. 45 (2–3): 91–97. doi:10.1016/S0166-445X(98)00112-X.
- ↑ Ankley GT, Brooks BW, Huggett DB, Sumpter JP (2007). "Repeating history: pharmaceuticals in the environment". Environmental Science & Technology. 41 (24): 8211–7. Bibcode:2007EnST...41.8211A. doi: 10.1021/es072658j . PMID 18200843.
- ↑ Kostich MS, Lazorchak JM (2008). "Risks to aquatic organisms posed by human pharmaceutical use". The Science of the Total Environment. 389 (2–3): 329–39. Bibcode:2008ScTEn.389..329K. doi:10.1016/j.scitotenv.2007.09.008. PMID 17936335.