[42] Druggability of SCF Ubiquitin Ligase–Protein Interfaces

The unique mechanism of the SCF ubiquitin ligase poses a challenge to drug discovery. A central enzymatic small molecule–binding active site is not evident in this multisubunit protein enzyme, as is the case with kinases or proteases. Instead, the SCF ligase seems to accomplish ubiquitylation through a series of cooperative movements dependent on the protein interfaces between its components and its substrate. Activity‐modulating small molecules, therefore, need to interact with these protein interfaces. The three‐dimensional structure of these interfaces may be the key asset in determining their suitability for small molecule binding. Computational tools and a systematic approach described in detail here can assess the ‘‘druggability’’ of an SCF ligase before the investment of effort in high‐throughput screening (HTS), structure‐based drug design (SBBD), or virtual library screening (VLS).