Drug Design Strategy Aims For Disorder

Drug designers should set their sights on small molecules that induce conformational disorder in their protein targets, according to Ariel Fernández and Alejandro Crespo of Rice University (Mol. Pharmaceutics, DOI: 10.1021/mp700148h). Most drug design strategies focus solely on promoting favorable nonbonding interactions between the drug and its protein target. As such, drug binding to a protein target often incurs an entropic penalty that arises primarily from the protein restricting its conformational freedom, or floppiness, to interact with the drug. Fernández and Crespo say their strategy marks "a departure from the order-upon-binding scenario" that typically characterizes drug design. As proof of concept, they used information gleaned from molecular dynamics simulations to rationally tweak the structure of the cancer drug imatinib (Gleevec) so the molecule would induce conformational disorder in one of the drug's major kinase targets upon binding. The disorder-inducing imatinib analog inhibits both the kinase and an imatinib-resistant version in several in vitro assays. "Induced disorder thus becomes a promising concept for drug design," they conclude.