Fragment Screening and Lead Evolution
Fragment-based drug discovery (FBDD) is becoming an increasingly efficient alternative to traditional high throughput screening of compound libraries in the pharmaceutical industry for the discovery of new chemical entities (NCEs). Most traditional fragment screening methods utilize physical methods such as NMR, surface plasmon resonance (SPR), and crystallography.
NMR and SPR fragment screening techniques measure molecular interactions between low affinity fragments and their target, and as such are highly susceptible to false positives arising from non-specific binding to an unrelated part of the drug target (protein or enzyme). Crystallography fragment screening yields fewer false positives, but is time-consuming and expensive.
Plex has successfully developed and optimized a cost-effective fragment screening platform based on assays that measure functional activity to greatly expedite the screening process and hit identification. Plex's function-based methodology exploits the biological function of drug targets to aid in identifying fragment hits with greater selectivity and specificity much earlier in the discovery process.
Fragment screening at Plex is performed utilizing a proprietary 1,000-member fragment library optimized for properties that have a higher probability of yielding blood brain barrier-crossing CNS “drug-like” NCEs.
Plex has also developed an advanced differential fragment screening (DFS) platform to distinguish hits against targets with related isotype forms. DFS has proved to be a particularly powerful tool for screening targets with closely related isotypes to identify highly isotype-selective inhibitors as well as pan inhibitors.
Plex's functional fragment screening platform, when combined with structural biology and X-ray crystallography, not only expedites but also yields “drug-like” leads superior in selectivity and specificity to leads identified by conventional SAR, while also offering the following added advantages:
- More efficient and higher throughput screening method for identifying hits
- Provides quantitative efficacy values of fragments in terms of Ki, Kd, IC50 or EC50
- Screening can be easily formatted for medium throughput to match the limited size of a typical fragment library without the need for expensive robotic systems
- False positives and non-specific binding is minimized with incorporation of proper controls
Plex Pharmaceuticals has successfully applied this approach to identify numerous low micro to low millimolar hits for a variety of drug targets to rapidly advance its internal drug discovery portfolio.