Fragment-based drug discovery using the SHAPES method

The SHAPES method is one of several fragment-based drug discovery methods developed in the last decade. Molecules containing drug-like fragments are screened using NMR methods to find weakly binding (0.1 μM to multi-mM) hits that are then transformed into potent, viable leads. This review analyzes ten years of SHAPES screens, in which potent leads were found for 70 - 80% of the targets screened, and discusses lessons learned about how best to apply fragment-based lead discovery in the pharmaceutical environment. Detailed examples of lead discovery and optimization for the kinases REDK and MK2 are given. Finally, future directions are considered and a strategy is proposed for increasing efficiency by coupling fragment-based screening with receptor-assisted inhibitor design (NMR-RAID).