Chemistry-Inspired Diffusion with Non-Differentiable Guidance

Recent advances in diffusion models have shown remarkable potential in the conditional generation of novel molecules. These models can be guided in two ways: (i) explicitly, through additional features representing the condition, or (ii) implicitly, using a property predictor. However, training property predictors or conditional diffusion models requires an abundance of labeled data and is inherently challenging in real-world applications. We propose a novel approach that attenuates the limitations of acquiring large labeled datasets by leveraging domain knowledge from quantum chemistry as a non-differentiable oracle to guide an unconditional diffusion model. Instead of relying on neural networks, the oracle provides accurate guidance in the form of estimated gradients, allowing the diffusion process to sample from a conditional distribution specified by quantum chemistry. We show that this results in more precise conditional generation of novel and stable molecular structures. Our experiments demonstrate that our method: (1) significantly reduces atomic forces, enhancing the validity of generated molecules when used for stability optimization; (2) is compatible with both explicit and implicit guidance in diffusion models, enabling joint optimization of molecular properties and stability; and (3) generalizes effectively to molecular optimization tasks beyond stability optimization. https://github.com/A-Chicharito-S/ChemGuide * Equal contribution.

† Correspondence to: Barnabás Póczos and Newell Washburn. 1 For example, LD50 (Erhirhie et al., 2018) measures the lethal dose of a test substance, which is difficult to calculate from the molecular structure of the substance alone; thus, requiring animal testing.