Allosteric binding cooperativity in a kinetic context
Allosteric modulators are of prime interest in drug discovery. These drugs regulate the binding and function of endogenous ligands, with some advantages over orthosteric ligands. A typical pharmacological parameter in allosteric modulation is binding cooperativity. This property can yield unexpected...
| Autores: | , , , , , |
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| Formato: | artículo |
| Fecha de publicación: | 2022 |
| País: | España |
| Recursos: | Universitat Politècnica de Catalunya (UPC) |
| Repositorio: | UPCommons. Portal del coneixement obert de la UPC |
| Idioma: | inglés |
| OAI Identifier: | oai:upcommons.upc.edu:2117/378432 |
| Acesso em linha: | https://hdl.handle.net/2117/378432 https://dx.doi.org/10.1016/j.drudis.2022.103441 |
| Access Level: | acceso abierto |
| Palavra-chave: | Drugs -- Mathematical models Allosteric modulation Binding kinetics Binding cooperativity: Rate constant Cooperativity rate constant Residence time GPCRs Heterodimer receptor Medicaments -- Models matemàtics Àrees temàtiques de la UPC::Matemàtiques i estadística::Matemàtica aplicada a les ciències |
| Resumo: | Allosteric modulators are of prime interest in drug discovery. These drugs regulate the binding and function of endogenous ligands, with some advantages over orthosteric ligands. A typical pharmacological parameter in allosteric modulation is binding cooperativity. This property can yield unexpected but illuminating results when decomposed into its kinetic parameters. Using two reference models (the allosteric ternary complex receptor model and a heterodimer receptor model), a relationship has been derived for the cooperativity rate constant parameters. This relationship allows many combinations of the cooperativity kinetic parameters for a single binding cooperativity value obtained under equilibrium conditions. This assessment may help understand striking experimental results involving allosteric modulation and suggest further investigations in the field |
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