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

Georges Vauquelin, David Hall, Steven Charlton

    Onderzoeksoutput: Articlepeer review

    10 Citaten (Scopus)

    Samenvatting

    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.
    Originele taal-2English
    Pagina's (van-tot)2300-2315
    TijdschriftBritish Journal of Pharmacology
    Volume172
    Nummer van het tijdschrift9
    Vroegere onlinedatum17 mrt 2015
    DOI's
    StatusPublished - mei 2015

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