MF-LAL: Drug Compound Generation Using Multi-Fidelity Latent Space Active Learning

Peter Eckmann, Dongxia Wu, Germano Heinzelmann, Michael K Gilson, Rose Yu

Keywords: drug discovery, multi-fidelity learning, generative models

Abstract: Current generative models for drug discovery primarily use molecular docking as an oracle to guide the generation of active compounds. However, such models are often not useful in practice because even compounds with high docking scores do not consistently show experimental activity. More accurate methods for activity prediction exist, such as molecular dynamics based binding free energy calculations, but they are too computationally expensive to use in a generative model. To address this challenge, we propose Multi-Fidelity Latent space Active Learning (MF-LAL), a generative modeling framework that integrates a set of oracles with varying cost-accuracy tradeoffs. We train a surrogate model for each oracle and use these surrogates to generate compounds with high predicted activity. Unlike previous approaches that separately learn the surrogate model and generative model, MF-LAL combines the generative and multi-fidelity surrogate models into a single framework, allowing for more accurate activity prediction and higher quality samples. We train MF-LAL with a novel active learning algorithm to further reduce computational cost. Our experiments on two disease-relevant proteins show that MF-LAL produces compounds with significantly better binding free energy scores than other single and multi-fidelity approaches.

Primary Area: applications to physical sciences (physics, chemistry, biology, etc.)

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Submission Number: 9367