structure-search

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:

1. Ring replacement: Bioisosteric substitution
2. Ring opening/closing: Modify topology
3. Linker modification: Change connectivity
4. 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

# Similarity search
python scripts/structure_search.py --query "SMILES" --threshold 0.7

# Scaffold analysis
python scripts/scaffold_analysis.py --input compounds.sdf --type murcko

# Scaffold hopping
python scripts/scaffold_hop.py --input compound.sdf --output hops.sdf

# Chemical space mapping
python scripts/chemical_space.py --library compounds.sdf --pca

Requirements

pip install rdkit pandas numpy scikit-learn

# Optional for visualization
pip install plotly seaborn matplotlib

Reference

• reference/fingerprints.md - Fingerprint reference
• reference/scaffold-methods.md - Scaffold methods
• reference/chemical-space.md - Chemical space analysis

Best Practices

1. Use appropriate thresholds: 0.7 for similar compounds
2. Consider scaffold: Different scaffold may have similar activity
3. Check properties: Similar doesn't mean drug-like
4. Validate experimentally: In-silico similarity needs confirmation
5. 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