Cooperativity as quantification and optimization paradigm for nuclear receptor modulators.

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 γ (PPARγ), 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 (K ^I _D) and NR-ligand binding (K ^II _D), jointly recapitulated in the cooperativity factor (α) for each specific ternary ligand·NR·coregu

SUBMITTER: de Vink PJ 

PROVIDER: S-EPMC8890100 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature