Biological target

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A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets are proteins and nucleic acids. The definition is context-dependent, and can refer to the biological target of a pharmacologically active drug compound, the receptor target of a hormone (like insulin), or some other target of an external stimulus. Biological targets are most commonly proteins such as enzymes, ion channels, and receptors.

Mechanism[edit]

The external stimulus (i.e., the drug or ligand) physically binds to ("hits") the biological target.[1][2] The interaction between the substance and the target may be:

  • noncovalent – A relatively weak interaction between the stimulus and the target where no chemical bond is formed between the two interacting partners and hence the interaction is completely reversible.
  • reversible covalent – A chemical reaction occurs between the stimulus and target in which the stimulus becomes chemically bonded to the target, but the reverse reaction also readily occurs in which the bond can be broken.
  • irreversible covalent – The stimulus is permanently bound to the target through irreversible chemical bond formation.

Depending on the nature of the stimulus, the following can occur:[3]

  • There is no direct change in the biological target, but the binding of the substance prevents other endogenous substances (such as activating hormones) from binding to the target. Depending on the nature of the target, this effect is referred as receptor antagonism, enzyme inhibition, or ion channel blockade.
  • A conformational change in the target is induced by the stimulus which results in a change in target function. This change in function can mimic the effect of the endogenous substance in which case the effect is referred to as receptor agonism (or channel or enzyme activation) or be the opposite of the endogenous substance which in the case of receptors is referred to as inverse agonism.

Drug targets[edit]

The term "biological target" is frequently used in pharmaceutical research to describe the native protein in the body whose activity is modified by a drug resulting in a specific effect, which may be a desirable therapeutic effect or an unwanted adverse effect. In this context, the biological target is often referred to as a drug target. The most common drug targets of currently marketed drugs include:[4][5][6]

Drug target identification[edit]

Identifying the biological origin of a disease, and the potential targets for intervention, is the first step in the discovery of a medicine using the reverse pharmacology approach. Potential drug targets are not necessarily disease causing but must by definition be disease modifying.[8] An alternative means of identifying new drug targets is forward pharmacology based on phenotypic screening to identify "orphan" ligands[9] whose targets are subsequently identified through target deconvolution.[10][11][12]

Databases[edit]

Databases containing biological targets information:

Conservation ecology[edit]

These biological targets are conserved across species, making pharmaceutical pollution of the environment a danger to species who possess the same targets.[13] For example, the synthetic estrogen in human contraceptives, 17-R-ethinylestradiol, has been shown to increase the feminization of fish downstream from sewage treatment plants, thereby unbalancing reproduction and creating an additional selective pressure on fish survival.[14] Pharmaceuticals are usually found at ng/L to lowµg/L concentrations in the aquatic environment.[15] Adverse effects may occur in non-target species as a consequence of specific drug target interactions.[16] Therefore, evolutionarily well-conserved drug targets are likely to be associated with an increased risk for non-targeted pharmacological effects.[13]

See also[edit]

References[edit]

  1. ^ 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.
  2. ^ Moy VT, Florin EL, Gaub HE (October 1994). "Intermolecular forces and energies between ligands and receptors". Science. 266 (5183): 257–9. doi:10.1126/science.7939660. PMID 7939660.
  3. ^ 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 0-7020-3471-1.
  4. ^ 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 0-7020-3471-1.
  5. ^ 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.
  6. ^ 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.
  7. ^ Lundstrom K (2009). "An overview on GPCRs and drug discovery: structure-based drug design and structural biology on GPCRs". Methods in Molecular Biology. 552: 51–66. doi:10.1007/978-1-60327-317-6_4. PMID 19513641.
  8. ^ 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.
  9. ^ 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. 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ a b 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): 580713. doi:10.1021/es8005173. PMID 18754513.
  14. ^ 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.
  15. ^ Ankley GT, Brooks BW, Huggett DB, Sumpter JP (2007). "Repeating history: pharmaceuticals in the environment". Environmental Science & Technology. 41 (24): 8211–7. doi:10.1021/es072658j. PMID 18200843.
  16. ^ 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. doi:10.1016/j.scitotenv.2007.09.008. PMID 17936335.
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