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\begin{document}

\title{Why classical receptor theory, which ignores allostery, can effectively
measure the strength of an allosteric effect as ligand efficacy}



\author[1]{Ongun Onaran}%
\author[2]{Tommaso Costa}%
\affil[1]{Ankara University Faculty of Medicine}%
\affil[2]{Istituto Superiore di Sanità}%


\vspace{-1em}



  
  \date{May 29, 2024}


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\begin{abstract}
Background and Purpose: The classical theory of receptor action has been
used for decades as a powerful tool to estimate molecular determinants
of ligand-induced receptor activation (i.e. affinity and efficacy) from
experimentally observable biological responses. However, it is also a
well-recognized fact that the receptor-binding and activation
mechanisms, and the parameters thereof, described in the classical
theory contradict with the modern view of receptor activation based on
allosteric principles. Experimental Approach: We used mathematical
analysis, along with some numerical simulations, to answer the key
question as to what extent the classical theory is compatible -if at
all- with the modern understanding of receptor activation. Key Results:
Here, we showed conclusively that 1) receptor activation equations based
on allosteric principles contain the logic of the classical theory in
disguise, and therefore, 2) estimates of ``intrinsic efficacy'' (?)
obtained by means of classical techniques (i.e. null methods or fitting
the operational model to concentration-response data) are equivalent to
the allosteric coupling factors that represent the molecular efficacy of
ligands. Conclusion and Implications: Thus, we conclude that despite the
right criticisms it has received so far, the classical theory may
continue to be useful in estimating ligand efficacy from experimental
data, if used properly. Here, we also provide rigorous criteria for the
proper use of the theory. These findings not only have implications on
ligand classification, but also resolve some long lasting discussions in
the field of bias agonism in GPCR, which requires reasonable estimates
of relative ligand efficacies at different signalling pathways.%
\end{abstract}%



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