Jeff Guo

Jeff Guo, Philippe Schwaller

Generative molecular design has moved from proof-of-concept to real-world applicability, as marked by the surge in very recent papers reporting experimental validation. Key challenges in explainability and sample efficiency present opportunities to enhance generative design to directly optimize expensive high-fidelity oracles and provide actionable insights to domain experts. Here, we propose Beam Enumeration to exhaustively enumerate the most probable sub-sequences from language-based molecular generative models and show that molecular substructures can be extracted. When coupled with reinforcement learning, extracted substructures become meaningful, providing a source of explainability and improving sample efficiency through self-conditioned generation. Beam Enumeration is generally applicable to any language-based molecular generative model and notably further improves the performance of the recently reported Augmented Memory algorithm, which achieved the new state-of-the-art on the Practical Molecular Optimization benchmark for sample efficiency. The combined algorithm generates more high reward molecules and faster, given a fixed oracle budget. Beam Enumeration shows that improvements to explainability and sample efficiency for molecular design can be made synergistic.

Anthony GX-Chen, Jatin Prakash, Jeff Guo et al.

It is commonly believed that optimizing the reverse KL divergence results in "mode seeking", while optimizing forward KL results in "mass covering", with the latter being preferred if the goal is to sample from multiple diverse modes. We show -- mathematically and empirically -- that this intuition does not necessarily transfer well to doing reinforcement learning with reverse/forward KL regularization (e.g. as commonly used with language models). Instead, the choice of reverse/forward KL determines the family of optimal target distributions, parameterized by the regularization coefficient. Mode coverage depends primarily on other factors, such as regularization strength, and relative scales between rewards and reference probabilities. Further, we show commonly used settings such as low regularization strength and equal verifiable rewards tend to specify unimodal target distributions, meaning the optimization objective is, by construction, non-diverse. We leverage these insights to construct a simple, scalable, and theoretically justified algorithm. It makes minimal changes to reward magnitudes, yet optimizes for a target distribution which puts high probability over all high-quality sampling modes. In experiments, this simple modification works to post-train both Large Language Models and Chemical Language Models to have higher solution quality and diversity, without any external signals of diversity, and works with both forward and reverse KL when using either naively fails.

Jeff Guo, Philippe Schwaller

Constrained synthesizability is an unaddressed challenge in generative molecular design. In particular, designing molecules satisfying multi-parameter optimization objectives, while simultaneously being synthesizable and enforcing the presence of specific commercial building blocks in the synthesis. This is practically important for molecule re-purposing, sustainability, and efficiency. In this work, we propose a novel reward function called TANimoto Group Overlap (TANGO), which uses chemistry principles to transform a sparse reward function into a dense and learnable reward function -- crucial for reinforcement learning. TANGO can augment general-purpose molecular generative models to directly optimize for constrained synthesizability while simultaneously optimizing for other properties relevant to drug discovery using reinforcement learning. Our framework is general and addresses starting-material, intermediate, and divergent synthesis constraints. Contrary to most existing works in the field, we show that incentivizing a general-purpose (without any inductive biases) model is a productive approach to navigating challenging optimization scenarios. We demonstrate this by showing that the trained models explicitly learn a desirable distribution. Our framework is the first generative approach to tackle constrained synthesizability.