Nuclear Receptors (NRs) are highly relevant drug targets, for which small molecule modulation goes beyond a simple ligand/receptor interaction. NR-ligands modulate Protein-Protein Interactions (PPIs) with coregulator proteins. Here we bring forward a cooperativity mechanism for small molecule modulation of NR PPIs, using the Peroxisome Proliferator Activated Receptor gamma (PPAR gamma), which describes NR-ligands as allosteric molecular glues. The cooperativity framework uses a thermodynamic model based on three-body binding events, to dissect and quantify reciprocal effects of NR-coregulator binding (KID) and NR-ligand binding (KIID), jointly recapitulated in the cooperativity factor (alpha) for each specific ternary ligand center dot NR center dot coregulator complex formation. These fundamental thermodynamic parameters allow for a conceptually new way of thinking about structure-activity-relationships for NR-ligands and can steer NR modulator discovery and optimization via a completely novel approach.

Cooperativity as quantification and optimization paradigm for nuclear receptor modulators

D'Arrigo, Giulia;Spyrakis, Francesca
;
2022-01-01

Abstract

Nuclear Receptors (NRs) are highly relevant drug targets, for which small molecule modulation goes beyond a simple ligand/receptor interaction. NR-ligands modulate Protein-Protein Interactions (PPIs) with coregulator proteins. Here we bring forward a cooperativity mechanism for small molecule modulation of NR PPIs, using the Peroxisome Proliferator Activated Receptor gamma (PPAR gamma), which describes NR-ligands as allosteric molecular glues. The cooperativity framework uses a thermodynamic model based on three-body binding events, to dissect and quantify reciprocal effects of NR-coregulator binding (KID) and NR-ligand binding (KIID), jointly recapitulated in the cooperativity factor (alpha) for each specific ternary ligand center dot NR center dot coregulator complex formation. These fundamental thermodynamic parameters allow for a conceptually new way of thinking about structure-activity-relationships for NR-ligands and can steer NR modulator discovery and optimization via a completely novel approach.
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de Vink, Pim J; Koops, Auke A; D'Arrigo, Giulia; Cruciani, Gabriele; Spyrakis, Francesca; Brunsveld, Luc
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1880346
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