Experimental Conditions to Retrieve Intrinsic Cooperativity α Directly from Single Binding Assay Data Exemplified by the Ternary Complex Formation of FKBP12, MAPRE1 and Macrocyclic Molecular Glues DOI Open Access
Jan Schnatwinkel, Richard R. Stein, Michael Salcius

и другие.

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(7), С. 2936 - 2936

Опубликована: Март 24, 2025

The incorporation of disease-relevant targets into ternary complexes in a compound-dependent manner by utilizing an assisting chaperone has become common modality as far bifunctional complex-forming compounds are concerned. In contrast, examples formed molecular glues much rarer. Due to their lack significant binary (independent) target affinity, identification cannot yet be achieved rational methods and is, therefore, more challenging. However, it is precisely for that reason (given the associated advantages) systematic application drug discovery recently attracted particular interest. contrast compounds, retrieve part thermodynamic stability through newly induced chaperone-target or glue-target interactions occur only complex. These lead enhanced ligand binding-termed intrinsic cooperativity α-which can retrieved via apparent either monitoring binding protein. this publication, advantage measuring (to determine α) weaker protein discussed illustrated using example between FKBP12, MAPRE1 macrocyclic derived from rapamycin motif FKBP12. Furthermore, impact following three parameters on illustrated: (1) concentration protein, (2) excess counter (3) affinity glue combination with degree α. From this, experimental conditions α one assay without need comprehensive mathematical model covering all simultaneous events under non-saturating highlighted. framework requires capable at least estimating very weak affinities. If not possible reasons, but assays both proteins available within normal bandwidth stronger too high, how curve presence used overcome missing Kd weakly

Язык: Английский

Experimental Conditions to Retrieve Intrinsic Cooperativity α Directly from Single Binding Assay Data Exemplified by the Ternary Complex Formation of FKBP12, MAPRE1 and Macrocyclic Molecular Glues DOI Open Access
Jan Schnatwinkel, Richard R. Stein, Michael Salcius

и другие.

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(7), С. 2936 - 2936

Опубликована: Март 24, 2025

The incorporation of disease-relevant targets into ternary complexes in a compound-dependent manner by utilizing an assisting chaperone has become common modality as far bifunctional complex-forming compounds are concerned. In contrast, examples formed molecular glues much rarer. Due to their lack significant binary (independent) target affinity, identification cannot yet be achieved rational methods and is, therefore, more challenging. However, it is precisely for that reason (given the associated advantages) systematic application drug discovery recently attracted particular interest. contrast compounds, retrieve part thermodynamic stability through newly induced chaperone-target or glue-target interactions occur only complex. These lead enhanced ligand binding-termed intrinsic cooperativity α-which can retrieved via apparent either monitoring binding protein. this publication, advantage measuring (to determine α) weaker protein discussed illustrated using example between FKBP12, MAPRE1 macrocyclic derived from rapamycin motif FKBP12. Furthermore, impact following three parameters on illustrated: (1) concentration protein, (2) excess counter (3) affinity glue combination with degree α. From this, experimental conditions α one assay without need comprehensive mathematical model covering all simultaneous events under non-saturating highlighted. framework requires capable at least estimating very weak affinities. If not possible reasons, but assays both proteins available within normal bandwidth stronger too high, how curve presence used overcome missing Kd weakly

Язык: Английский

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