TDC Molecule Generation Oracles

TDC Molecule Generation Oracles

Oracles are functions that evaluate the quality of generated molecules across specific dimensions. TDC provides 17+ oracle functions for molecular optimization tasks in de novo drug design.

Overview

Oracles measure molecular properties and serve two main purposes:

1. Goal-Directed Generation: Optimize molecules to maximize/minimize specific properties
2. Distribution Learning: Evaluate whether generated molecules match desired property distributions

Using Oracles

Basic Usage

from tdc import Oracle

# Initialize oracle
oracle = Oracle(name='GSK3B')

# Evaluate single molecule (SMILES string)
score = oracle('CC(C)Cc1ccc(cc1)C(C)C(O)=O')

# Evaluate multiple molecules
scores = oracle(['SMILES1', 'SMILES2', 'SMILES3'])

Oracle Categories

TDC oracles are organized into several categories based on the molecular property being evaluated.

Biochemical Oracles

Predict binding affinity or activity against biological targets.

Target-Specific Oracles

DRD2 - Dopamine Receptor D2

oracle = Oracle(name='DRD2')
score = oracle(smiles)

• Measures binding affinity to DRD2 receptor
• Important for neurological and psychiatric drug development
• Higher scores indicate stronger binding

GSK3B - Glycogen Synthase Kinase-3 Beta

oracle = Oracle(name='GSK3B')
score = oracle(smiles)

• Predicts GSK3β inhibition
• Relevant for Alzheimer's, diabetes, and cancer research
• Higher scores indicate better inhibition

JNK3 - c-Jun N-terminal Kinase 3

oracle = Oracle(name='JNK3')
score = oracle(smiles)

• Measures JNK3 kinase inhibition
• Target for neurodegenerative diseases
• Higher scores indicate stronger inhibition

5HT2A - Serotonin 2A Receptor

oracle = Oracle(name='5HT2A')
score = oracle(smiles)

• Predicts serotonin receptor binding
• Important for psychiatric medications
• Higher scores indicate stronger binding

ACE - Angiotensin-Converting Enzyme

oracle = Oracle(name='ACE')
score = oracle(smiles)

• Measures ACE inhibition
• Target for hypertension treatment
• Higher scores indicate better inhibition

MAPK - Mitogen-Activated Protein Kinase

oracle = Oracle(name='MAPK')
score = oracle(smiles)

• Predicts MAPK inhibition
• Target for cancer and inflammatory diseases

CDK - Cyclin-Dependent Kinase

oracle = Oracle(name='CDK')
score = oracle(smiles)

• Measures CDK inhibition
• Important for cancer drug development

P38 - p38 MAP Kinase

oracle = Oracle(name='P38')
score = oracle(smiles)

• Predicts p38 MAPK inhibition
• Target for inflammatory diseases

PARP1 - Poly (ADP-ribose) Polymerase 1

oracle = Oracle(name='PARP1')
score = oracle(smiles)

• Measures PARP1 inhibition
• Target for cancer treatment (DNA repair mechanism)

PIK3CA - Phosphatidylinositol-4,5-Bisphosphate 3-Kinase

oracle = Oracle(name='PIK3CA')
score = oracle(smiles)

• Predicts PIK3CA inhibition
• Important target in oncology

Physicochemical Oracles

Evaluate drug-like properties and ADME characteristics.

Drug-Likeness Oracles

QED - Quantitative Estimate of Drug-likeness

oracle = Oracle(name='QED')
score = oracle(smiles)

• Combines multiple physicochemical properties
• Score ranges from 0 (non-drug-like) to 1 (drug-like)
• Based on Bickerton et al. criteria

Lipinski - Rule of Five

oracle = Oracle(name='Lipinski')
score = oracle(smiles)

• Number of Lipinski rule violations
• Rules: MW ≤ 500, logP ≤ 5, HBD ≤ 5, HBA ≤ 10
• Score of 0 means fully compliant

Molecular Properties

SA - Synthetic Accessibility

oracle = Oracle(name='SA')
score = oracle(smiles)

• Estimates ease of synthesis
• Score ranges from 1 (easy) to 10 (difficult)
• Lower scores indicate easier synthesis

LogP - Octanol-Water Partition Coefficient

oracle = Oracle(name='LogP')
score = oracle(smiles)

• Measures lipophilicity
• Important for membrane permeability
• Typical drug-like range: 0-5

MW - Molecular Weight

oracle = Oracle(name='MW')
score = oracle(smiles)

• Returns molecular weight in Daltons
• Drug-like range typically 150-500 Da

Composite Oracles

Combine multiple properties for multi-objective optimization.

Isomer Meta

oracle = Oracle(name='Isomer_Meta')
score = oracle(smiles)

• Evaluates specific isomeric properties
• Used for stereochemistry optimization

Median Molecules

oracle = Oracle(name='Median1', 'Median2')
score = oracle(smiles)

• Tests ability to generate molecules with median properties
• Useful for distribution learning benchmarks

Rediscovery

oracle = Oracle(name='Rediscovery')
score = oracle(smiles)

• Measures similarity to known reference molecules
• Tests ability to regenerate existing drugs

Similarity

oracle = Oracle(name='Similarity')
score = oracle(smiles)

• Computes structural similarity to target molecules
• Based on molecular fingerprints (typically Tanimoto similarity)

Uniqueness

oracle = Oracle(name='Uniqueness')
scores = oracle(smiles_list)

• Measures diversity in generated molecule set
• Returns fraction of unique molecules

Novelty

oracle = Oracle(name='Novelty')
scores = oracle(smiles_list, training_set)

• Measures how different generated molecules are from training set
• Higher scores indicate more novel structures

Specialized Oracles

ASKCOS - Retrosynthesis Scoring

oracle = Oracle(name='ASKCOS')
score = oracle(smiles)

• Evaluates synthetic feasibility using retrosynthesis
• Requires ASKCOS backend (IBM RXN)
• Scores based on retrosynthetic route availability

Docking Score

oracle = Oracle(name='Docking')
score = oracle(smiles)

• Molecular docking score against target protein
• Requires protein structure and docking software
• Lower scores typically indicate better binding

Vina - AutoDock Vina Score

oracle = Oracle(name='Vina')
score = oracle(smiles)

• Uses AutoDock Vina for protein-ligand docking
• Predicts binding affinity in kcal/mol
• More negative scores indicate stronger binding

Multi-Objective Optimization

Combine multiple oracles for multi-property optimization:

from tdc import Oracle

# Initialize multiple oracles
qed_oracle = Oracle(name='QED')
sa_oracle = Oracle(name='SA')
drd2_oracle = Oracle(name='DRD2')

# Define custom scoring function
def multi_objective_score(smiles):
    qed = qed_oracle(smiles)
    sa = 1 / (1 + sa_oracle(smiles))  # Invert SA (lower is better)
    drd2 = drd2_oracle(smiles)

    # Weighted combination
    return 0.3 * qed + 0.3 * sa + 0.4 * drd2

# Evaluate molecule
score = multi_objective_score('CC(C)Cc1ccc(cc1)C(C)C(O)=O')

Oracle Performance Considerations

Speed

• Fast: QED, SA, LogP, MW, Lipinski (rule-based calculations)
• Medium: Target-specific ML models (DRD2, GSK3B, etc.)
• Slow: Docking-based oracles (Vina, ASKCOS)

Reliability

• Oracles are ML models trained on specific datasets
• May not generalize to all chemical spaces
• Use multiple oracles to validate results

Batch Processing

# Efficient batch evaluation
oracle = Oracle(name='GSK3B')
smiles_list = ['SMILES1', 'SMILES2', ..., 'SMILES1000']
scores = oracle(smiles_list)  # Faster than individual calls

Common Workflows

Goal-Directed Generation

from tdc import Oracle
from tdc.generation import MolGen

# Load training data
data = MolGen(name='ChEMBL_V29')
train_smiles = data.get_data()['Drug'].tolist()

# Initialize oracle
oracle = Oracle(name='GSK3B')

# Generate molecules (user implements generative model)
# generated_smiles = generator.generate(n=1000)

# Evaluate generated molecules
scores = oracle(generated_smiles)
best_molecules = [(s, score) for s, score in zip(generated_smiles, scores)]
best_molecules.sort(key=lambda x: x[1], reverse=True)

print(f"Top 10 molecules:")
for smiles, score in best_molecules[:10]:
    print(f"{smiles}: {score:.3f}")

Distribution Learning

from tdc import Oracle
import numpy as np

# Initialize oracle
oracle = Oracle(name='QED')

# Evaluate training set
train_scores = oracle(train_smiles)
train_mean = np.mean(train_scores)
train_std = np.std(train_scores)

# Evaluate generated set
gen_scores = oracle(generated_smiles)
gen_mean = np.mean(gen_scores)
gen_std = np.std(gen_scores)

# Compare distributions
print(f"Training: μ={train_mean:.3f}, σ={train_std:.3f}")
print(f"Generated: μ={gen_mean:.3f}, σ={gen_std:.3f}")

Integration with TDC Benchmarks

from tdc.generation import MolGen

# Use with GuacaMol benchmark
data = MolGen(name='GuacaMol')

# Oracles are automatically integrated
# Each GuacaMol task has associated oracle
benchmark_results = data.evaluate_guacamol(
    generated_molecules=your_molecules,
    oracle_name='GSK3B'
)

Notes

• Oracle scores are predictions, not experimental measurements
• Always validate top candidates experimentally
• Different oracles may have different score ranges and interpretations
• Some oracles require additional dependencies or API access
• Check oracle documentation for specific details: https://tdcommons.ai/functions/oracles/

Adding Custom Oracles

To create custom oracle functions:

class CustomOracle:
    def __init__(self):
        # Initialize your model/method
        pass

    def __call__(self, smiles):
        # Implement your scoring logic
        # Return score or list of scores
        pass

# Use like built-in oracles
custom_oracle = CustomOracle()
score = custom_oracle('CC(C)Cc1ccc(cc1)C(C)C(O)=O')

References

• TDC Oracles Documentation: https://tdcommons.ai/functions/oracles/
• GuacaMol Paper: "GuacaMol: Benchmarking Models for de Novo Molecular Design"
• MOSES Paper: "Molecular Sets (MOSES): A Benchmarking Platform for Molecular Generation Models"