Druggability: Structural and Translational Perspectives
1. What Is Druggability?
Druggability refers to the potential of a biological target to be modulated by a drug-like molecule in a way that produces a therapeutic effect. It encompasses structural compatibility, functional relevance, and clinical feasibility.
2. Structural Features
- Binding Pocket Characteristics: Size, shape, depth, and hydrophobicity influence ligand compatibility.
- Allosteric Sites: Enable selective modulation beyond conserved active sites.
- Cryptic Sites: Transient pockets revealed through conformational dynamics or fragment binding.
3. Biophysical and Biochemical Properties
- Ligand Efficiency Metrics: LE, LLE, and FQ assess binding quality relative to molecular size and lipophilicity.
- Target Flexibility: Dynamic proteins may require stabilization of specific conformers.
- Surface Accessibility: Determines feasibility of targeting membrane-bound or intracellular proteins.
4. Biological Relevance
- Functional Modulation: Binding must alter activity meaningfully (inhibition, activation, degradation).
- Pathway Integration: Target should influence disease-relevant signaling cascades.
- Tissue Selectivity: Preferential expression in diseased tissue reduces off-target effects.
5. Assessing Druggability
| Method | Purpose | Example |
|---|---|---|
| X-ray / cryo-EM | Visualize pocket architecture | Kinase inhibitor binding modes |
| Fragment Screening | Identify weak-binding fragments | Cryptic sites in bromodomains |
| Molecular Dynamics | Explore pocket flexibility | Allosteric sites in GPCRs |
| Computational Scoring | Quantify druggability (e.g., SiteMap) | Virtual screening prioritization |
| AI Prediction Models | Integrate structure + omics | Rare disease target discovery |
6. Expanding Druggability
- Protein–Protein Interactions: Targeted via hot spot mapping, stapled peptides, and molecular glues.
- RNA Targets: Structured motifs (e.g., hairpins) enable small molecule or oligonucleotide targeting.
- Targeted Protein Degradation: PROTACs and molecular glues expand druggability beyond inhibition.
7. Strategic Implications
- Target Prioritization: Druggability scores guide early-stage decisions.
- Modality Selection: Informs choice between small molecules, biologics, or nucleic acid therapies.
- Risk Assessment: Low druggability may require novel chemistry or alternative modalities.