Induced disorder in protein-ligand complexes as a drug-design strategy.

Protein associations are poorly understood from a chemical perspective. If the contrary were true, drug inhibitors would be routinely designed based on target structure. While enthalpy/entropy balance is critical for affinity optimization, most drug-design strategies focus solely on promoting favorable intermolecular interactions. However, protein-drug associations often entail an entropic penalty, mostly arising from induced fits, which compromises affinity. Rather than restricting the conformational freedom of the protein, this work reports on an alternative design strategy to enhance affinity by inducing conformational disorder. This approach is adopted to target kinases by boosting their conformational entropy, taking advantage of their structural plasticity. As proof of concept we redesigned the anticancer drug imatinib to inhibit the imatinib-resistant D816V mutant of the C-Kit kinase, one of imatinib's primary targets. The prototype is engineered to promote an entropic boost on the activation loop that restores affinity. We also show that induced disorder is actually operational in kinase inhibitory action: a comparison of the binding of imatinib and PD173955 to Bcr-Abl kinase reveals that imatinib forms stronger intermolecular nonbonded interactions than PD173955, yet the latter binds with higher affinity by boosting the complex entropy. Induced disorder thus becomes a promising concept for drug design.