| name | structure-search |
| description | Structure-based similarity search and scaffold analysis for drug discovery.
Use for lead hopping, scaffold morphing, and chemical space exploration.
Keywords: similarity search, scaffold hopping, chemical space, fingerprint, Tanimoto
|
| category | Computational Chemistry |
| tags | ["structure","similarity","fingerprint","scaffold","chemical-space"] |
| version | 1.0.0 |
| author | Drug Discovery Team |
| dependencies | ["rdkit","chembl","pubchem"] |
Structure Search Skill
Structure-based similarity search and scaffold analysis for drug discovery.
Quick Start
/structure --query "CC1=CC=C(C=C1)CNC" --threshold 0.7
/scaffold-hop --input compound.sdf --scaffold-type murcko
/similar-compounds --chembl "CHEMBL210" --limit 20
Similarity Methods
Fingerprint-Based
| Fingerprint | Size | Best Use | Speed |
|---|
| Morgan | 2048 | General purpose | Fast |
| MACCS | 166 | General purpose | Very fast |
| RDKit | 2048 | Structural features | Fast |
| Atom pair | 2048 | Substructure | Medium |
| Topological torsion | 2048 | Conformations | Medium |
Similarity Coefficients
| Coefficient | Range | Properties |
|---|
| Tanimoto | 0-1 | Most common, bounded |
| Dice | 0-1 | Similar to Tanimoto |
| Cosine | 0-1 | Vector-based |
| Tversky | 0-1 | Asymmetric |
Scaffold Analysis
Scaffold Types
| Type | Definition | Use Case |
|---|
| Murcko | Core ring system | General |
| Bemis-Murcko | Rings + linkers | Drug-like |
| RECAP | Rings + functional groups | Medicinal chemistry |
| Graph | Only topology | Very generic |
Scaffold Hopping
Strategies:
- Ring replacement: Bioisosteric substitution
- Ring opening/closing: Modify topology
- Linker modification: Change connectivity
- Heteroatom swap: N→O→S→C
Output Structure
# Structure Search Results
## Query Compound
**SMILES**: CC1=CC=C(C=C1)CNC
**Name**: Erlotinib
**Scaffold**: c1ccc(cc1)CNCC
## Similar Compounds (Tanimoto ≥ 0.7)
| Rank | ID | Name | Similarity | Scaffold Match |
|------|----|-----|------------|----------------|
| 1 | CHEMBL210 | Erlotinib | 1.00 | Yes |
| 2 | CHEMBL214 | Gefitinib | 0.89 | Yes |
| 3 | CHEMBL617 | Afatinib | 0.82 | Yes |
| 4 | CHEMBL12345 | Novel analog | 0.76 | No |
| 5 | CHEMBL98765 | Lead compound | 0.72 | Yes |
## Scaffold Analysis
### Murcko Scaffold
Query: c1ccc(cc1)CNCC (Quinazoline core)
### Known Compounds with This Scaffold
| Compound | Class | Status |
|----------|-------|--------|
| Erlotinib | 1st-gen TKI | Approved |
| Gefitinib | 1st-gen TKI | Approved |
| Afatinib | 2nd-gen TKI | Approved |
| Dacomitinib | 2nd-gen TKI | Approved |
| Osimertinib | 3rd-gen TKI | Approved |
### Scaffold Frequency
| Scaffold | ChEMBL Count | Use |
|----------|--------------|-----|
| Quinazoline | 2,456 | Kinase inhibitors |
| Pyrimidine | 3,789 | Various targets |
| Pyrrolopyrimidine | 456 | Selective kinases |
## Scaffold Hopping Opportunities
### Ring Replacements
| Original | Bioisostere | Rationale |
|----------|-------------|-----------|
| Benzene | Pyridine | Add H-bond acceptor |
| Benzene | Thiophene | Slightly larger, polarizable |
| Pyridine | Pyrimidine | Add H-bond acceptor |
| Phenyl | Cyclohexyl | Remove aromaticity |
### Novel Scaffolds
**Identified 3 novel scaffolds** with similar topology:
1. **Indazole core**: 3 compounds
2. **Pyrrolopyrimidine**: 5 compounds
3. **Imidazopyridazine**: 2 compounds
## Property Comparison
| Property | Query | Mean (Similar) | Range |
|----------|-------|----------------|-------|
| MW | 393 | 420 | 350-480 |
| LogP | 3.2 | 3.5 | 2.8-4.2 |
| HBD | 1 | 1.2 | 1-2 |
| HBA | 3 | 3.5 | 2-5 |
| PSA | 72 | 78 | 65-95 |
## Recommendations
1. **Explore indazole compounds**: Novel scaffold, good properties
2. **Monitor pyrrolopyrimidines**: Emerging scaffold
3. **Consider scaffold hopping**: If IP crowded
Similarity Thresholds
| Application | Tanimoto | Interpretation |
|---|
| Identical | 1.0 | Same compound |
| Very similar | 0.9-1.0 | Same analog series |
| Similar | 0.7-0.9 | Same scaffold |
| Related | 0.5-0.7 | Similar structure |
| Distant | 0.3-0.5 | Some similarity |
| Unrelated | <0.3 | Different chemotypes |
Running Scripts
python scripts/structure_search.py --query "SMILES" --threshold 0.7
python scripts/scaffold_analysis.py --input compounds.sdf --type murcko
python scripts/scaffold_hop.py --input compound.sdf --output hops.sdf
python scripts/chemical_space.py --library compounds.sdf --pca
Requirements
pip install rdkit pandas numpy scikit-learn
pip install plotly seaborn matplotlib
Reference
Best Practices
- Use appropriate thresholds: 0.7 for similar compounds
- Consider scaffold: Different scaffold may have similar activity
- Check properties: Similar doesn't mean drug-like
- Validate experimentally: In-silico similarity needs confirmation
- Use multiple methods: Fingerprints + alignment for full picture
Common Pitfalls
| Pitfall | Solution |
|---|
| High similarity ≠ same activity | Check bioactivity |
| Ignoring stereochemistry | Use isomeric SMILES |
| Fingerprint bias | Try multiple fingerprint types |
| Scaffold blindness | Explicit scaffold analysis |
| Over-clustering | Appropriate threshold selection |
