Goal-directed optimization is essential for steering molecular generators to propose candidates with desired properties. However, it is often implemented with policy-gradient reinforcement learning, which requires a generation-trajectory log-probability whose form depends on the model architecture and generation procedure. This makes an optimizer difficult to reuse across architectures and conditional generative designs. Supervised fine-tuning needs none of that machinery, but its update is driven by a fixed dataset, so the reward never enters the update. We introduce Elite-Weighted Supervised Fine-tuning (EW-SFT), which uses reward to guide elite selection of high-scoring molecules, and updates the model by its own pretraining loss on that set. Ablations show that reward information is passed primarily through elite selection, rather than through continuous weighting within the selected set. Because the update consumes only scored molecules and the model's native loss, the same rule applies across autoregressive, masked-diffusion, and discrete-flow generators, and across de novo, motif-extension, and linker-design tasks. Under a fixed budget of 3D shape alignment oracle calls on two kinase reference compounds, EW-SFT consistently outperforms the corresponding native optimizers. It further improves goal-directed optimization under a 2D similarity oracle on four held-out references and achieves comparable performance on a sample-efficiency benchmark without a trajectory-level RL formulation. These results demonstrate that EW-SFT is a unified and effective optimizer across molecular generators, design constraints, references, and oracles.
Boqiao Zhang, Godbless James, Sai Krishna Gottipati +1cs.LG cs.AI
Improving molecular properties, such as drug-likeness or binding affinity, is a recurring task in early-stage drug discovery. However, molecules optimized in an unconstrained chemical space have limited practical value if they cannot be synthesized. Policy Gradient for Forward Synthesis (PGFS) is a synthesis-aware reinforcement learning method for molecular improvement, but its use of reactant embedding prediction makes reactant selection indirect, which, as we show, limits learning effectiveness. We first develop PGFS+, in which reaction templates and second reactants are represented by trainable embedding lookup tables. Combined with a more effective scoring function and RL algorithm, PGFS+ significantly improves the desired property. However, it exposes a reward-hacking failure mode: a powerful reactant search can map diverse input molecules to the same high-reward magnet molecule, improving the reward while collapsing the output diversity. We therefore introduce PGFS++, a synthesis-aware reinforcement learning framework for input-specific molecular improvement. Given an input molecule, PGFS++ treats it as the start of a forward-synthesis trajectory, applies learned reaction templates with compatible in-stock building blocks, and produces a molecule with improved target properties, an explicit synthesis route, and structural similarity to the input. Experiments on molecular improvement tasks show that PGFS++ improves target properties while preserving high output diversity.
Scientific discovery often involves optimising expensive-to-evaluate objectives over vast, structured, and open-ended hypothesis spaces, such as molecules, protein sequences, and computer programs. Generative models such as large language models (LLMs) provide expressive priors over such spaces, but their likelihoods and self-assessments are unreliable proxies for the objectives and calibrated epistemic uncertainty, especially for novel candidates outside the observed data distribution. We introduce the Large Discovery Model (LDM), an empirically grounded recurrent architecture that couples a generative model with a Bayesian non-parametric reward surrogate model. The generative model proposes and refines candidate designs, while the surrogate predicts their performance and quantifies uncertainty, yielding an uncertainty-aware value that guides candidate generation, refinement, and selection. The discovery memory and the surrogate model are continually updated as each new experimental observation arrives. We evaluate LDM on three scenarios spanning different design modalities and objectives, including neural-network training, antibody design, and molecular optimisation. Compared to LLM-only reflection or traditional statistical search across these domains, LDM achieves a $2.4\times$ greater reduction in validation BPB, an $18.2\%$ relative decrease in binding energy, and more than $60\%$ relative gains in molecular multi-objective performance. These results suggests that LDM could serve as a general-purpose discovery engine for effective search over open-ended hypothesis spaces.
Molecular optimization is commonly performed under a limited oracle budget, which makes deciding what to evaluate as important as deciding what to generate. We introduce short-term graph memory, a plug-in module that preserves the generator architecture and native update rule while learning from previously evaluated molecules to prioritize subsequent oracle queries. The module maintains an online graph neural surrogate that pre-screens each round's candidate pool, so the fixed oracle budget is spent on molecules with higher predicted utility. Applied to a fragment-based generator on a standard molecular optimization benchmark, it improves the mean top-10 score at no extra oracle cost and never falls behind the base on any oracle; the gain extends to all four generators we tested at a tight budget of one thousand calls. We then analyze how surrogate-guided selection interacts with the exploration and exploitation behavior of different generators. Its benefit at larger budgets is consistent with two properties of the backbone: how broadly it searches, and how effectively its native search already exploits oracle feedback. We provide a simple way to spend a fixed oracle budget more selectively, and evidence on which generators benefit from it.
Oracle-limited molecular optimization gives reward only after a complete molecule is generated, while each rollout requires many local next-token decisions. This delayed-feedback interface makes molecular policy optimization myopic: an optimizer can learn that a molecule was good without knowing which intermediate actions made it good. We introduce Q-Steer, a rollout-time action-value steering primitive for molecular language models. Q-Steer uses an offline-trained and frozen prefix-action value scorer, PAVS-Q, that estimates the downstream reward of taking a candidate next token under a partial SMILES prefix, then adds a normalized value bonus to sampling logits. The optimizer update rule and online oracle budget are unchanged; the claim is fixed-online-oracle performance, not equal total compute. On PMO23 with a fixed 10,000-call online budget, complete factorial studies across two molecular language-model backbones and four optimizers show that Q-Steer improves mean valid-unique score in all eight backbone-optimizer cells, with positive macro mean-score gains between +0.033 and +0.049 and 18-20 task wins per cell. Mechanism controls show that action identity matters: prefix-broadcast values are nearly neutral, while shuffled action values harm performance. These results support Q-Steer as a reusable rollout-time action-value wrapper that improves average molecular optimization reward across optimizer families and policy backbones without changing the online oracle budget.
Jaewook Lee, Ethan Errington, Christian D. Lorenz +1cs.LG
Self-driving laboratories increasingly rely on multi-fidelity Bayesian optimization (MFBO) to balance cheap, approximate evaluations against scarce, expensive ones, with a predictive surrogate at its core. Gaussian processes (GPs) are the default choice, but they scale poorly as data accumulate and assume a smooth landscape that molecular and materials search spaces routinely violate. Transfer learning offers an alternative suited to this regime: it learns a representation from abundant cheap data and adapts it to sparse expensive data. Despite its use in property prediction, transfer learning has not been tested as the engine of a closed-loop optimization. Here we benchmark eleven transfer-learning surrogates against four GP methods under an identical selection rule, fidelity budget, and model size, across nine tasks spanning synthetic functions to real chemistry and materials problems. GPs win on smooth, low-dimensional functions but perform worst on molecular and materials problems, where transfer-learning surrogates reach substantially better solutions using far less computation. Because acquisition policy is held fixed across surrogates, this advantage is attributable to the surrogate itself. Uncertainty-driven exploration is not reliably beneficial, and calibration does not predict optimization performance, so greedy exploitation of the transfer-learned mean is the more robust default. Transfer learning is therefore the surrogate of choice for molecular and materials MFBO.
Sarina Kopf, Cristina Nevado, Philippe Schwallercs.LG
Molecular optimization in drug discovery, materials design, and catalysis requires searching vast chemical spaces under tight evaluation budgets, since high-fidelity oracles and experimental measurements are costly. The practical impact of an optimization method therefore hinges on its sample efficiency: how few evaluations it needs to find strong candidates. We introduce Sample Efficient Generative Optimization (SEGO), a framework for Bayesian optimization on adaptively generated molecules. In SEGO, a probabilistic surrogate model forms a hypothesis about where hits lie in chemical space, a generative model is steered to propose candidates in that region, the most promising candidate is selected via an acquisition function, and the resulting oracle call is used both to sharpen the surrogate and to anchor the generator in real reward. SEGO attains state-of-the-art performance on the practical molecular optimization (PMO) benchmark using only one tenth of the oracle calls consumed by other methods, and on a multiparameter docking task it reaches ten hits in roughly half the oracle calls of existing approaches. These gains move molecular optimization closer to campaigns driven by direct experimental feedback.
Molecular optimization often starts from a pretrained generative model that captures a broad prior over valid molecular structures. At test time, however, the goal is not to sample from this prior, but to use a limited oracle budget to shift generation toward task-specific high-reward molecules. We study this adaptation problem for discrete diffusion models. Each online round couples several choices. The loop must decide which candidates to evaluate, how rewards become model updates, which feedback to reuse, and how far to move beyond the pretrained prior. These choices have mostly been studied in isolation, leaving open whether they complement one another, become redundant, or interfere inside a full online adaptation loop. We conduct controlled studies across six small-molecule binding-affinity tasks and three protein-fitness tasks. We find that acquisition, reward shaping, and model debiasing provide complementary routes to higher reward, especially for small molecules. Replay further stabilizes learning, while validity penalties keep small-molecule exploration on the valid molecular manifold. Together, these findings point to a practical recipe for feedback-efficient molecular optimization: online fine-tuning with acquisition, reward shaping, debiasing, replay, and validity control. This recipe outperforms offline fine-tuning and inference-time search baselines under matched oracle-call budgets and GPU-hour accounting. The gains are largest when high-reward candidates require larger shifts from the pretrained prior.
Scientific reasoning is an increasingly important capability of large language models, yet improving the robustness and efficiency of training such reasoning remains a key open challenge. We study this problem in instruction-based molecular optimization, where answer-only supervised fine-tuning (SFT) collapses multi-step reasoning and reinforcement learning with verifiable rewards (RLVR) suffers from sparse feedback. Reference-guided Policy Optimization mitigates both by anchoring policy updates to dataset-provided references, but its effectiveness is tightly coupled to reference quality: weak or misaligned references impose a performance ceiling. To overcome this ceiling, we propose active reasoning, a paradigm in which the policy actively decides, on a per-instance basis, when to imitate a reference and when to reinforce its own discoveries, while continuously upgrading what it imitates. We instantiate this paradigm as Active Group Relative Policy Optimization (Active-GRPO), realized through two coupled mechanisms: active imitate-reinforce and active referencing. The former performs imitation learning when the reference still outperforms the policy's own candidates, and shifts to self-improvement via reinforcement learning once the policy has generated molecules that surpass the reference. The latter continuously upgrades the reference itself by replacing it with the best policy-generated candidate discovered so far, progressively raising the imitation target and ensuring that reference guidance remains informative-rather than restrictive-throughout training. Across TOMG-Bench MOLOPT, Active-GRPO improves average SRxSim from 0.0959 for GRPO and 0.1665 for RePO to 0.1773 under matched three-seed evaluation, with statistically significant gains on LogP, MR, and QED.
Generative molecular design is shaped by simple proxy benchmarks for drug-like properties and models pretrained on large pharmaceutical datasets. This combination yields strong benchmark metrics but limits transferability to domains structurally distinct from drug discovery. To overcome this limitation and drive discovery toward real, scientifically grounded targets, we introduce the Nanotechnology Molecular Optimization (NMO) Benchmark, which bridges machine learning (ML) and quantum materials science. NMO acts simultaneously as a rigorous testbed for the ML community and a discovery engine for nanotechnology research. The suite replaces proxy oracles with quantum simulations and introduces strict protocols that prioritize scientific utility over leaderboard-oriented overfitting. The physics-based NMO tasks impose hard structural constraints and rugged fitness landscapes, posing fundamentally new requirements on generative models. Notably, advanced molecular optimization methods underperform much simpler approaches on the NMO tasks. We develop a new baseline method identifying the critical components to solve the NMO tasks, including a novel representation for modeling structural constraints and a domain-agnostic pretraining strategy to eliminate pharmaceutical dataset bias. Our results surpass state-of-the-art physical properties and reveal previously unknown structural motifs, offering new insights for the nanotechnology community and demonstrating that ML can drive genuine scientific discovery.
Black-box optimization problems remain challenging because of large, weakly structured, and high-dimensional search spaces. Existing methods often suffer from poor sample efficiency because they rely on direct candidate generation or trial-and-error refinement. A natural way to improve search efficiency is to use world modeling, which can help identify promising optimization directions before costly evaluation. Large language models can predict the outcomes of these candidates with nontrivial accuracy because of their implicit knowledge. Motivated by this observation, we propose WMLLM, a self-evolving optimization-agent framework based on predict-then-act world modeling. The agent first predicts promising directions and then acts to generate candidates. Combined with agentic multi-turn refinement, population-based search, and reinforcement learning, WMLLM refines both its implicit world model and its optimization strategy during search. Experiments on black-box optimization tasks, especially multi-objective molecular optimization, show that WMLLM improves sample efficiency and final optimization performance. On the multi-objective molecular optimization benchmark, WMLLM achieves state-of-the-art results under a limited evaluation budget.