@synsci/cli-darwin-x64-baseline 1.1.76 → 1.1.78

package/bin/skills/drugbank-database/references/chemical-analysis.md

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+# Chemical Properties and Similarity Analysis
+
+## Overview
+DrugBank provides extensive chemical property data including molecular structures, physicochemical properties, and calculated descriptors. This information enables structure-based analysis, similarity searches, and QSAR modeling.
+
+## Chemical Identifiers and Structures
+
+### Available Structure Formats
+- **SMILES**: Simplified Molecular Input Line Entry System
+- **InChI**: International Chemical Identifier
+- **InChIKey**: Hashed InChI for database searching
+- **Molecular Formula**: Chemical formula (e.g., C9H8O4)
+- **IUPAC Name**: Systematic chemical name
+- **Traditional Names**: Common names and synonyms
+
+### Extract Chemical Structures
+```python
+from drugbank_downloader import get_drugbank_root
+
+def get_drug_structures(drugbank_id):
+    """Extract chemical structure representations"""
+    root = get_drugbank_root()
+    ns = {'db': 'http://www.drugbank.ca'}
+
+    for drug in root.findall('db:drug', ns):
+        primary_id = drug.find('db:drugbank-id[@primary="true"]', ns)
+        if primary_id is not None and primary_id.text == drugbank_id:
+            structures = {}
+
+            # Get calculated properties
+            calc_props = drug.find('db:calculated-properties', ns)
+            if calc_props is not None:
+                for prop in calc_props.findall('db:property', ns):
+                    kind = prop.find('db:kind', ns).text
+                    value = prop.find('db:value', ns).text
+
+                    if kind in ['SMILES', 'InChI', 'InChIKey', 'Molecular Formula', 'IUPAC Name']:
+                        structures[kind] = value
+
+            return structures
+    return {}
+
+# Usage
+structures = get_drug_structures('DB00001')
+print(f"SMILES: {structures.get('SMILES')}")
+print(f"InChI: {structures.get('InChI')}")
+```
+
+## Physicochemical Properties
+
+### Calculated Properties
+Properties computed from structure:
+- **Molecular Weight**: Exact mass in Daltons
+- **logP**: Partition coefficient (lipophilicity)
+- **logS**: Aqueous solubility
+- **Polar Surface Area (PSA)**: Topological polar surface area
+- **H-Bond Donors**: Number of hydrogen bond donors
+- **H-Bond Acceptors**: Number of hydrogen bond acceptors
+- **Rotatable Bonds**: Number of rotatable bonds
+- **Refractivity**: Molar refractivity
+- **Polarizability**: Molecular polarizability
+
+### Experimental Properties
+Measured properties from literature:
+- **Melting Point**: Physical melting point
+- **Water Solubility**: Experimental solubility data
+- **pKa**: Acid dissociation constant
+- **Hydrophobicity**: Experimental logP/logD values
+
+### Extract All Properties
+```python
+def get_all_properties(drugbank_id):
+    """Extract all calculated and experimental properties"""
+    root = get_drugbank_root()
+    ns = {'db': 'http://www.drugbank.ca'}
+
+    for drug in root.findall('db:drug', ns):
+        primary_id = drug.find('db:drugbank-id[@primary="true"]', ns)
+        if primary_id is not None and primary_id.text == drugbank_id:
+            properties = {
+                'calculated': {},
+                'experimental': {}
+            }
+
+            # Calculated properties
+            calc_props = drug.find('db:calculated-properties', ns)
+            if calc_props is not None:
+                for prop in calc_props.findall('db:property', ns):
+                    kind = prop.find('db:kind', ns).text
+                    value = prop.find('db:value', ns).text
+                    source = prop.find('db:source', ns)
+                    properties['calculated'][kind] = {
+                        'value': value,
+                        'source': source.text if source is not None else None
+                    }
+
+            # Experimental properties
+            exp_props = drug.find('db:experimental-properties', ns)
+            if exp_props is not None:
+                for prop in exp_props.findall('db:property', ns):
+                    kind = prop.find('db:kind', ns).text
+                    value = prop.find('db:value', ns).text
+                    properties['experimental'][kind] = value
+
+            return properties
+    return {}
+
+# Usage
+props = get_all_properties('DB00001')
+print(f"Molecular Weight: {props['calculated'].get('Molecular Weight', {}).get('value')}")
+print(f"logP: {props['calculated'].get('logP', {}).get('value')}")
+```
+
+## Lipinski's Rule of Five Analysis
+
+### Rule of Five Checker
+```python
+def check_lipinski_rule_of_five(drugbank_id):
+    """Check if drug satisfies Lipinski's Rule of Five"""
+    props = get_all_properties(drugbank_id)
+    calc_props = props.get('calculated', {})
+
+    # Extract values
+    mw = float(calc_props.get('Molecular Weight', {}).get('value', 0))
+    logp = float(calc_props.get('logP', {}).get('value', 0))
+    h_donors = int(calc_props.get('H Bond Donor Count', {}).get('value', 0))
+    h_acceptors = int(calc_props.get('H Bond Acceptor Count', {}).get('value', 0))
+
+    # Check rules
+    rules = {
+        'molecular_weight': mw <= 500,
+        'logP': logp <= 5,
+        'h_bond_donors': h_donors <= 5,
+        'h_bond_acceptors': h_acceptors <= 10
+    }
+
+    violations = sum(1 for passes in rules.values() if not passes)
+
+    return {
+        'passes': violations <= 1,  # Allow 1 violation
+        'violations': violations,
+        'rules': rules,
+        'values': {
+            'molecular_weight': mw,
+            'logP': logp,
+            'h_bond_donors': h_donors,
+            'h_bond_acceptors': h_acceptors
+        }
+    }
+
+# Usage
+ro5 = check_lipinski_rule_of_five('DB00001')
+print(f"Passes Ro5: {ro5['passes']} (Violations: {ro5['violations']})")
+```
+
+### Veber's Rules
+```python
+def check_veber_rules(drugbank_id):
+    """Check Veber's rules for oral bioavailability"""
+    props = get_all_properties(drugbank_id)
+    calc_props = props.get('calculated', {})
+
+    psa = float(calc_props.get('Polar Surface Area (PSA)', {}).get('value', 0))
+    rotatable = int(calc_props.get('Rotatable Bond Count', {}).get('value', 0))
+
+    rules = {
+        'polar_surface_area': psa <= 140,
+        'rotatable_bonds': rotatable <= 10
+    }
+
+    return {
+        'passes': all(rules.values()),
+        'rules': rules,
+        'values': {
+            'psa': psa,
+            'rotatable_bonds': rotatable
+        }
+    }
+```
+
+## Chemical Similarity Analysis
+
+### Structure-Based Similarity with RDKit
+```python
+from rdkit import Chem
+from rdkit.Chem import AllChem, DataStructs
+
+def calculate_tanimoto_similarity(smiles1, smiles2):
+    """Calculate Tanimoto similarity between two molecules"""
+    mol1 = Chem.MolFromSmiles(smiles1)
+    mol2 = Chem.MolFromSmiles(smiles2)
+
+    if mol1 is None or mol2 is None:
+        return None
+
+    # Generate Morgan fingerprints (ECFP4)
+    fp1 = AllChem.GetMorganFingerprintAsBitVect(mol1, 2, nBits=2048)
+    fp2 = AllChem.GetMorganFingerprintAsBitVect(mol2, 2, nBits=2048)
+
+    # Calculate Tanimoto similarity
+    similarity = DataStructs.TanimotoSimilarity(fp1, fp2)
+    return similarity
+
+# Usage
+struct1 = get_drug_structures('DB00001')
+struct2 = get_drug_structures('DB00002')
+
+similarity = calculate_tanimoto_similarity(
+    struct1.get('SMILES'),
+    struct2.get('SMILES')
+)
+print(f"Tanimoto similarity: {similarity:.3f}")
+```
+
+### Find Similar Drugs
+```python
+def find_similar_drugs(reference_drugbank_id, similarity_threshold=0.7):
+    """Find structurally similar drugs in DrugBank"""
+    root = get_drugbank_root()
+    ns = {'db': 'http://www.drugbank.ca'}
+
+    # Get reference structure
+    ref_structures = get_drug_structures(reference_drugbank_id)
+    ref_smiles = ref_structures.get('SMILES')
+
+    if not ref_smiles:
+        return []
+
+    similar_drugs = []
+
+    for drug in root.findall('db:drug', ns):
+        drug_id = drug.find('db:drugbank-id[@primary="true"]', ns).text
+
+        if drug_id == reference_drugbank_id:
+            continue
+
+        # Get SMILES
+        drug_structures = get_drug_structures(drug_id)
+        drug_smiles = drug_structures.get('SMILES')
+
+        if drug_smiles:
+            similarity = calculate_tanimoto_similarity(ref_smiles, drug_smiles)
+
+            if similarity and similarity >= similarity_threshold:
+                drug_name = drug.find('db:name', ns).text
+                indication = drug.find('db:indication', ns)
+                indication_text = indication.text if indication is not None else None
+
+                similar_drugs.append({
+                    'drug_id': drug_id,
+                    'drug_name': drug_name,
+                    'similarity': similarity,
+                    'indication': indication_text
+                })
+
+    # Sort by similarity
+    similar_drugs.sort(key=lambda x: x['similarity'], reverse=True)
+    return similar_drugs
+
+# Find similar drugs
+similar = find_similar_drugs('DB00001', similarity_threshold=0.7)
+for drug in similar[:10]:
+    print(f"{drug['drug_name']}: {drug['similarity']:.3f}")
+```
+
+### Batch Similarity Matrix
+```python
+import numpy as np
+import pandas as pd
+
+def create_similarity_matrix(drug_ids):
+    """Create pairwise similarity matrix for a list of drugs"""
+    n = len(drug_ids)
+    matrix = np.zeros((n, n))
+
+    # Get all SMILES
+    smiles_dict = {}
+    for drug_id in drug_ids:
+        structures = get_drug_structures(drug_id)
+        smiles_dict[drug_id] = structures.get('SMILES')
+
+    # Calculate similarities
+    for i, drug1_id in enumerate(drug_ids):
+        for j, drug2_id in enumerate(drug_ids):
+            if i == j:
+                matrix[i, j] = 1.0
+            elif i < j:  # Only calculate upper triangle
+                smiles1 = smiles_dict[drug1_id]
+                smiles2 = smiles_dict[drug2_id]
+
+                if smiles1 and smiles2:
+                    sim = calculate_tanimoto_similarity(smiles1, smiles2)
+                    matrix[i, j] = sim if sim is not None else 0
+                    matrix[j, i] = matrix[i, j]  # Symmetric
+
+    df = pd.DataFrame(matrix, index=drug_ids, columns=drug_ids)
+    return df
+
+# Create similarity matrix for a set of drugs
+drug_list = ['DB00001', 'DB00002', 'DB00003', 'DB00005']
+sim_matrix = create_similarity_matrix(drug_list)
+```
+
+## Molecular Fingerprints
+
+### Generate Different Fingerprint Types
+```python
+from rdkit.Chem import MACCSkeys
+from rdkit.Chem.AtomPairs import Pairs
+from rdkit.Chem.Fingerprints import FingerprintMols
+
+def generate_fingerprints(smiles):
+    """Generate multiple types of molecular fingerprints"""
+    mol = Chem.MolFromSmiles(smiles)
+    if mol is None:
+        return None
+
+    fingerprints = {
+        'morgan_fp': AllChem.GetMorganFingerprintAsBitVect(mol, 2, nBits=2048),
+        'maccs_keys': MACCSkeys.GenMACCSKeys(mol),
+        'topological_fp': FingerprintMols.FingerprintMol(mol),
+        'atom_pairs': Pairs.GetAtomPairFingerprint(mol)
+    }
+
+    return fingerprints
+
+# Generate fingerprints for a drug
+structures = get_drug_structures('DB00001')
+fps = generate_fingerprints(structures.get('SMILES'))
+```
+
+### Substructure Search
+```python
+from rdkit.Chem import Fragments
+
+def search_substructure(substructure_smarts):
+    """Find drugs containing a specific substructure"""
+    root = get_drugbank_root()
+    ns = {'db': 'http://www.drugbank.ca'}
+
+    pattern = Chem.MolFromSmarts(substructure_smarts)
+    if pattern is None:
+        print("Invalid SMARTS pattern")
+        return []
+
+    matching_drugs = []
+
+    for drug in root.findall('db:drug', ns):
+        drug_id = drug.find('db:drugbank-id[@primary="true"]', ns).text
+        structures = get_drug_structures(drug_id)
+        smiles = structures.get('SMILES')
+
+        if smiles:
+            mol = Chem.MolFromSmiles(smiles)
+            if mol and mol.HasSubstructMatch(pattern):
+                drug_name = drug.find('db:name', ns).text
+                matching_drugs.append({
+                    'drug_id': drug_id,
+                    'drug_name': drug_name
+                })
+
+    return matching_drugs
+
+# Example: Find drugs with benzene ring
+benzene_drugs = search_substructure('c1ccccc1')
+print(f"Found {len(benzene_drugs)} drugs with benzene ring")
+```
+
+## ADMET Property Prediction
+
+### Predict Absorption
+```python
+def predict_oral_absorption(drugbank_id):
+    """Predict oral absorption based on physicochemical properties"""
+    props = get_all_properties(drugbank_id)
+    calc_props = props.get('calculated', {})
+
+    mw = float(calc_props.get('Molecular Weight', {}).get('value', 0))
+    logp = float(calc_props.get('logP', {}).get('value', 0))
+    psa = float(calc_props.get('Polar Surface Area (PSA)', {}).get('value', 0))
+    h_donors = int(calc_props.get('H Bond Donor Count', {}).get('value', 0))
+
+    # Simple absorption prediction
+    good_absorption = (
+        mw <= 500 and
+        -0.5 <= logp <= 5.0 and
+        psa <= 140 and
+        h_donors <= 5
+    )
+
+    absorption_score = 0
+    if mw <= 500:
+        absorption_score += 25
+    if -0.5 <= logp <= 5.0:
+        absorption_score += 25
+    if psa <= 140:
+        absorption_score += 25
+    if h_donors <= 5:
+        absorption_score += 25
+
+    return {
+        'predicted_absorption': 'good' if good_absorption else 'poor',
+        'absorption_score': absorption_score,
+        'properties': {
+            'molecular_weight': mw,
+            'logP': logp,
+            'psa': psa,
+            'h_donors': h_donors
+        }
+    }
+```
+
+### BBB Permeability Prediction
+```python
+def predict_bbb_permeability(drugbank_id):
+    """Predict blood-brain barrier permeability"""
+    props = get_all_properties(drugbank_id)
+    calc_props = props.get('calculated', {})
+
+    mw = float(calc_props.get('Molecular Weight', {}).get('value', 0))
+    logp = float(calc_props.get('logP', {}).get('value', 0))
+    psa = float(calc_props.get('Polar Surface Area (PSA)', {}).get('value', 0))
+    h_donors = int(calc_props.get('H Bond Donor Count', {}).get('value', 0))
+
+    # BBB permeability criteria (simplified)
+    bbb_permeable = (
+        mw <= 450 and
+        logp <= 5.0 and
+        psa <= 90 and
+        h_donors <= 3
+    )
+
+    return {
+        'bbb_permeable': bbb_permeable,
+        'properties': {
+            'molecular_weight': mw,
+            'logP': logp,
+            'psa': psa,
+            'h_donors': h_donors
+        }
+    }
+```
+
+## Chemical Space Analysis
+
+### Principal Component Analysis
+```python
+from sklearn.decomposition import PCA
+from sklearn.preprocessing import StandardScaler
+
+def perform_chemical_space_pca(drug_ids):
+    """Perform PCA on chemical descriptor space"""
+    # Extract properties for all drugs
+    properties_list = []
+    valid_ids = []
+
+    for drug_id in drug_ids:
+        props = get_all_properties(drug_id)
+        calc_props = props.get('calculated', {})
+
+        try:
+            prop_vector = [
+                float(calc_props.get('Molecular Weight', {}).get('value', 0)),
+                float(calc_props.get('logP', {}).get('value', 0)),
+                float(calc_props.get('Polar Surface Area (PSA)', {}).get('value', 0)),
+                int(calc_props.get('H Bond Donor Count', {}).get('value', 0)),
+                int(calc_props.get('H Bond Acceptor Count', {}).get('value', 0)),
+                int(calc_props.get('Rotatable Bond Count', {}).get('value', 0)),
+            ]
+            properties_list.append(prop_vector)
+            valid_ids.append(drug_id)
+        except (ValueError, TypeError):
+            continue
+
+    # Perform PCA
+    X = np.array(properties_list)
+    scaler = StandardScaler()
+    X_scaled = scaler.fit_transform(X)
+
+    pca = PCA(n_components=2)
+    X_pca = pca.fit_transform(X_scaled)
+
+    # Create DataFrame
+    df = pd.DataFrame({
+        'drug_id': valid_ids,
+        'PC1': X_pca[:, 0],
+        'PC2': X_pca[:, 1]
+    })
+
+    return df, pca
+
+# Visualize chemical space
+# drug_list = [all approved drugs]
+# pca_df, pca_model = perform_chemical_space_pca(drug_list)
+```
+
+### Clustering by Chemical Properties
+```python
+from sklearn.cluster import KMeans
+
+def cluster_drugs_by_properties(drug_ids, n_clusters=10):
+    """Cluster drugs based on chemical properties"""
+    properties_list = []
+    valid_ids = []
+
+    for drug_id in drug_ids:
+        props = get_all_properties(drug_id)
+        calc_props = props.get('calculated', {})
+
+        try:
+            prop_vector = [
+                float(calc_props.get('Molecular Weight', {}).get('value', 0)),
+                float(calc_props.get('logP', {}).get('value', 0)),
+                float(calc_props.get('Polar Surface Area (PSA)', {}).get('value', 0)),
+                int(calc_props.get('H Bond Donor Count', {}).get('value', 0)),
+                int(calc_props.get('H Bond Acceptor Count', {}).get('value', 0)),
+            ]
+            properties_list.append(prop_vector)
+            valid_ids.append(drug_id)
+        except (ValueError, TypeError):
+            continue
+
+    X = np.array(properties_list)
+    scaler = StandardScaler()
+    X_scaled = scaler.fit_transform(X)
+
+    # K-means clustering
+    kmeans = KMeans(n_clusters=n_clusters, random_state=42)
+    clusters = kmeans.fit_predict(X_scaled)
+
+    df = pd.DataFrame({
+        'drug_id': valid_ids,
+        'cluster': clusters
+    })
+
+    return df, kmeans
+```
+
+## Export Chemical Data
+
+### Create Chemical Property Database
+```python
+def export_chemical_properties(output_file='drugbank_chemical_properties.csv'):
+    """Export all chemical properties to CSV"""
+    root = get_drugbank_root()
+    ns = {'db': 'http://www.drugbank.ca'}
+
+    all_properties = []
+
+    for drug in root.findall('db:drug', ns):
+        drug_id = drug.find('db:drugbank-id[@primary="true"]', ns).text
+        drug_name = drug.find('db:name', ns).text
+
+        props = get_all_properties(drug_id)
+        calc_props = props.get('calculated', {})
+
+        property_dict = {
+            'drug_id': drug_id,
+            'drug_name': drug_name,
+            'smiles': calc_props.get('SMILES', {}).get('value'),
+            'inchi': calc_props.get('InChI', {}).get('value'),
+            'inchikey': calc_props.get('InChIKey', {}).get('value'),
+            'molecular_weight': calc_props.get('Molecular Weight', {}).get('value'),
+            'logP': calc_props.get('logP', {}).get('value'),
+            'psa': calc_props.get('Polar Surface Area (PSA)', {}).get('value'),
+            'h_donors': calc_props.get('H Bond Donor Count', {}).get('value'),
+            'h_acceptors': calc_props.get('H Bond Acceptor Count', {}).get('value'),
+            'rotatable_bonds': calc_props.get('Rotatable Bond Count', {}).get('value'),
+        }
+
+        all_properties.append(property_dict)
+
+    df = pd.DataFrame(all_properties)
+    df.to_csv(output_file, index=False)
+    print(f"Exported {len(all_properties)} drug properties to {output_file}")
+
+# Usage
+export_chemical_properties()
+```
+
+## Best Practices
+
+1. **Structure Validation**: Always validate SMILES/InChI before use with RDKit
+2. **Multiple Descriptors**: Use multiple fingerprint types for comprehensive similarity
+3. **Threshold Selection**: Tanimoto >0.85 = very similar, 0.7-0.85 = similar, <0.7 = different
+4. **Rule Application**: Lipinski's Ro5 and Veber's rules are guidelines, not absolute cutoffs
+5. **ADMET Prediction**: Use computational predictions as screening, validate experimentally
+6. **Chemical Space**: Visualize chemical space to understand drug diversity
+7. **Standardization**: Standardize molecules (neutralize, remove salts) before comparison
+8. **Performance**: Cache computed fingerprints for large-scale similarity searches