orthosteric site
Definition:
The orthosteric site of an enzyme or receptor is the location to which the endogenous or natural agonist binds.
Relevance:
Orthosteric drugs bind at the orthosteric site and therefore compete with the natural substrate. Thus, these drugs can out-compete the native substrate, blocking the site, and ultimately affect the activity of the enzyme or receptor. Furthermore, as these sites tend to be highly conserved within certain protein families, orthosteric drugs that bind to the orthosteric site of one protein may also bind to those of homologous proteins.
In terms of drug development, specificity is crucial. To get high specificity in orthosteric drugs, they must have high affinity to the enzyme or receptor’s orthosteric site. Doing this minimizes potential unwanted adverse effects by limiting the drug from possibly binding to similar binding sites on proteins that are not the target protein.
Linked terms: Ligand, Substrate, Receptor, Enzyme, Binding Affinity, Competitive Inhibition
Resources:
Katritch, V., Cherezov, V. & Stevens, R. C. Structure-function of the G protein-coupled receptor superfamily. Annu. Rev. Pharmacol. Toxicol. 53, 531–556 (2013).
Neubig, R. R., Spedding, M., Kenakin, T., & Christopoulos, A. (2003, December). International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on Terms and Symbols in Quantitative Pharmacology. Pharmacological Reviews, 55(4), 597–606. https://doi.org/10.1124/pr.55.4.4
Nussinov, R., & Tsai, C. J. (2012). The different ways through which specificity works in orthosteric and allosteric drugs. Current pharmaceutical design, 18(9), 1311–1316. https://doi.org/10.2174/138161212799436377
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