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"Partial" competition of heterobivalent ligand binding may be mistaken for allosteric interactions: A comparison of different target interaction models

Tijdschriftbijdrage - Tijdschriftartikel

Background and Purpose: Non-competitive drugs that confer allosteric modulation of orthosteric ligand binding are of increasing interest as therapeutic agents. Sought-after advantages include a ceiling level to the drug effect and greater receptor subtype-selectivity. It is thus important to determine the mode of interaction of newly identified receptor ligands early in the drug discovery process and binding studies with labeled orthosteric ligands constitute a traditional approach thereto. According to the general allosteric ternary complex model, allosteric ligands that exhibit negative cooperativity may generate distinctive "competition" curves: they will not reach baseline levels and their nadir will increase in par with the orthosteric ligand concentration. This behavior is often considered as a key hallmark of allosteric interactions.
Experimental Approach: The present study is based on differential equation- based simulations.
Key Results: The same "competition binding" pattern can also be obtained when a monovalent ligand binds to one of the target sites of a heterobivalent ligand, even if this process is strictly competitive in nature. Interestingly, this pattern is also reciprocal; i.e. it occurs when the binding of each of those ligands is recorded. It is also shown that its prominence of this phenomenon may vary from one heterobivalent ligand to another and it is suggested that this phenomenon may take place with ligands whose binding complies with "two-domain" and "charnière" models.
Conclusions and Implications: The present findings extend the list of situations where purely competitive interactions may give rise to experimental observations that could be inadvertently be interpreted as allosteric binding.
Tijdschrift: Br. J. Pharmacol.
ISSN: 0007-1188
Issue: 9
Volume: 172
Pagina's: 2300-2315
Jaar van publicatie:2015
Trefwoorden:Allosteric modulation, Non-competitivity, Bivalent ligands, Competition binding, Differential equations, Simulations
  • Scopus Id: 84920604046
  • WoS Id: 000352809900010
CSS-citation score:1