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A P P L I C A T I O N N O T E
"I see the chaperone agnostic approach as more viable, especially for
addressing difficult targets, where the only way of modulating them is
their involvement into a ternary complex"
- Dr. Hans-Jörg Roth
THE IMPORTANCE OF COOPERATIVITY IN DRUG DESIGN
Hans-Jörg also underscores the critical role of cooperativity for proximity-inducing drugs. In classic
drug discovery, high affinity and therefore high specificity for a given target was o en achieved by
increasing the size of the molecule, and thereby the number of molecular interactions with the
protein. "Cooperativity plays a key role in ensuring that the molecular weight of the compound can
be kept low," Hans-Jörg notes. This is important because smaller compounds tend to have fewer side
effects compared to larger bifunctional molecules. A high cooperativity means that the chaperone
and the target form many stabilizing interactions that occur only in the ternary complex, leading
to higher potency. However, rationally designing for high cooperativity requires the availability of
a 3D-model, ideally coming from an X-ray or NMR structure of the ternary complex. Even then it
remains challenging. Hans-Jörg observes that computational methods are emerging, which —
crucially for the rational improvement of cooperativity — can handle the more complex molecular
dynamics of ternary complexes, as opposed to binary ligand-protein complexes.
U S E R C A S E S T U D Y
