Enhancer and competitive allosteric modulation model for G-protein coupled receptors

Daniele Pietra (1) , Alice Borghini (2) , Maria Cristina Breschi (3) , Anna Maria Bianucci (2)

1 Dipartimento di Medicina Interna - University of Pisa - Via Roma
2 Dipartimento di Scienze Farmaceutiche - University of Pisa - Via Bonanno
3 Dipartimento di Psichiatria

A new mathematical model, referred to as Enhancer and Competitive Allosteric Modulator (ECAM) model, developed with the aim of quantitatively describing the interaction of an allosteric modulator with both enhancer and competitive properties towards G-protein coupled receptors is described here. Model simulations for equilibrium (displacement-like, saturation-like), and kinetic (association, dissociation) binding experiments were performed. The results showed the ability of the model to interpret a number of possible ligand-receptor binding behaviors. In particular, the binding properties of PD81723, an enhancer and competitive allosteric modulator for the adenosine A receptor, were experimentally evaluated by radioligand binding assays and interpreted by the ECAM model. The results also offer a theoretical background enabling the design and optimization of compounds endowed with allosteric enhancer, competitive, agonist, antagonist, inverse agonist properties.

Mots clés: Ligand-receptor interactions; Allosterism; Drug screening; PD81723

Daniele Pietra, Alice Borghini, Maria Cristina Breschi, Anna Maria Bianucci. Enhancer and competitive allosteric modulation model for G-protein coupled receptors. Journal of Theoretical Biology, 2010, 267 (4), pp.663. ⟨10.1016/j.jtbi.2010.08.024⟩. ⟨hal-00637806⟩