Hide and Seek: Assessing Druggability and Uncovering Cryptic Pockets
Only around 20% of the human proteome has been successfully targeted by small molecules to date—leaving many therapeutically promising proteins labelled as “undruggable.” At Sygnature Discovery, we explore how computational chemistry can uncover hidden opportunities for intervention through cryptic pocket identification and advanced in silico modelling. In this poster, we present a case study on the E2 enzyme Cdc34, illustrating how our tools and expertise can reveal novel binding sites to support early-stage drug discovery.
Our In Silico Approach to Druggability
For novel or challenging targets, cryptic binding sites—transient or hidden pockets not visible in static crystal structures—offer a promising route to therapeutic modulation. Our Cdc34 case study highlights how:
- Cryptic pockets can be sampled directly and detected with a bioinformatics approach
- Novel, elusive sites may emerge during conformational sampling, ranking and screening
- Once identified, these pockets support hypothesis generation and ligand design
Cdc34 Case Study: Unlocking a Cryptic Pocket
Using the E2 enzyme Cdc34, we demonstrate how advanced molecular dynamics and in silico modelling can uncover hidden binding sites—transforming “undruggable” proteins into viable therapeutic targets.
Key Highlights from the Cdc34 Case Study:
- Cryptic pocket formation was triggered by conformational changes (~2 Å shift in the α2 helix) revealed through multistep MD simulations using Xenon probes and normal mode analysis.
- Advanced sampling techniques, including Weighted Ensemble MD (WEMD) and Exposon Analysis, enabled precise mapping and characterisation of the transient binding site.
- Ligand docking and refinement using ICM-Pro and short STMD simulations validated the cryptic pocket’s druggability, with the known inhibitor CC0651 adopting a stable and biologically relevant binding pose.
Download the full poster to explore how our computational druggability workflows, demonstrated through Cdc34, are helping to uncover new possibilities for therapeutic intervention.
At Sygnature Discovery, our multidisciplinary teams bring together computational innovation and deep domain expertise to accelerate your journey from novel target to validated hit. Speak to us today to learn how we can uncover your encrypted target next.