Frazier N. Baker

Botao Yu, Frazier N. Baker, Ziqi Chen et al.

Chemistry plays a crucial role in many domains, such as drug discovery and material science. While large language models (LLMs) such as GPT-4 exhibit remarkable capabilities on natural language processing tasks, existing research indicates that their performance on chemistry tasks is discouragingly low. In this paper, however, we demonstrate that our developed LLMs can achieve very strong results on a comprehensive set of chemistry tasks, outperforming the most advanced GPT-4 and Claude 3 Opus by a substantial margin. To accomplish this, we propose SMolInstruct, a large-scale, comprehensive, and high-quality dataset for instruction tuning. It contains 14 selected chemistry tasks and over three million samples, laying a solid foundation for training and evaluating LLMs for chemistry. Using SMolInstruct, we fine-tune a set of open-source LLMs, among which, we find that Mistral serves as the best base model for chemistry tasks. Our analysis further demonstrates the critical role of the proposed dataset in driving the performance improvements.

Reza Averly, Frazier N. Baker, Ian A. Watson et al.

Drug discovery is a long, expensive, and complex process, relying heavily on human medicinal chemists, who can spend years searching the vast space of potential therapies. Recent advances in artificial intelligence for chemistry have sought to expedite individual drug discovery tasks; however, there remains a critical need for an intelligent agent that can navigate the drug discovery process. Towards this end, we introduce LIDDIA, an autonomous agent capable of intelligently navigating the drug discovery process in silico. By leveraging the reasoning capabilities of large language models, LIDDIA serves as a low-cost and highly-adaptable tool for autonomous drug discovery. We comprehensively examine LIDDIA , demonstrating that (1) it can generate molecules meeting key pharmaceutical criteria on over 70% of 30 clinically relevant targets, (2) it intelligently balances exploration and exploitation in the chemical space, and (3) it identifies one promising novel candidate on AR/NR3C4, a critical target for both prostate and breast cancers. Code and dataset are available at https://github.com/ninglab/LIDDiA

Frazier N. Baker, Ziqi Chen, Daniel Adu-Ampratwum et al.

Retrosynthesis is the process of determining the set of reactant molecules that can react to form a desired product. Semi-template-based retrosynthesis methods, which imitate the reverse logic of synthesis reactions, first predict the reaction centers in the products, and then complete the resulting synthons back into reactants. We develop a new offline-online reinforcement learning method RLSynC for synthon completion in semi-template-based methods. RLSynC assigns one agent to each synthon, all of which complete the synthons by conducting actions step by step in a synchronized fashion. RLSynC learns the policy from both offline training episodes and online interactions, which allows RLSynC to explore new reaction spaces. RLSynC uses a standalone forward synthesis model to evaluate the likelihood of the predicted reactants in synthesizing a product, and thus guides the action search. Our results demonstrate that RLSynC can outperform state-of-the-art synthon completion methods with improvements as high as 14.9%, highlighting its potential in synthesis planning.

Frazier N. Baker, Trieu Nguyen, Reza Averly et al.

Multi-objective retrosynthesis planning is a critical chemistry task requiring dynamic balancing of quality, safety, and cost objectives. Language model-based multi-agent systems (MAS) offer a promising approach for this task: leveraging interactions of specialized agents to incorporate multiple objectives into retrosynthesis planning. We present MMORF, a framework for constructing MAS for multi-objective retrosynthesis planning. MMORF features modular agentic components, which can be flexibly combined and configured into different systems, enabling principled evaluation and comparison of different system designs. Using MMORF, we construct two representative MAS: MASIL and RFAS. On a newly curated benchmark consisting of 218 multi-objective retrosynthesis planning tasks, MASIL achieves strong safety and cost metrics on soft-constraint tasks, frequently Pareto-dominating baseline routes, while RFAS achieves a 48.6% success rate on hard-constraint tasks, outperforming state-of-the-art baselines. Together, these results show the effectiveness of MMORF as a foundational framework for exploring MAS for multi-objective retrosynthesis planning. Code and data are available at https://anonymous.4open.science/r/MMORF/.

Botao Yu, Frazier N. Baker, Ziru Chen et al.

To enhance large language models (LLMs) for chemistry problem solving, several LLM-based agents augmented with tools have been proposed, such as ChemCrow and Coscientist. However, their evaluations are narrow in scope, leaving a large gap in understanding the benefits of tools across diverse chemistry tasks. To bridge this gap, we develop ChemToolAgent, an enhanced chemistry agent over ChemCrow, and conduct a comprehensive evaluation of its performance on both specialized chemistry tasks and general chemistry questions. Surprisingly, ChemToolAgent does not consistently outperform its base LLMs without tools. Our error analysis with a chemistry expert suggests that: For specialized chemistry tasks, such as synthesis prediction, we should augment agents with specialized tools; however, for general chemistry questions like those in exams, agents' ability to reason correctly with chemistry knowledge matters more, and tool augmentation does not always help.

Frazier N. Baker, Daniel Adu-Ampratwum, Reza Averly et al.

Large language model (LLM) agent evaluators leverage specialized tools to ground the rational decision-making of LLMs, making them well-suited to aid in scientific discoveries, such as constrained retrosynthesis planning. Constrained retrosynthesis planning is an essential, yet challenging, process within chemistry for identifying synthetic routes from commercially available starting materials to desired target molecules, subject to practical constraints. Here, we present LARC, the first LLM-based Agentic framework for Retrosynthesis planning under Constraints. LARC incorporates agentic constraint evaluation, through an Agent-as-a-Judge, directly into the retrosynthesis planning process, using agentic feedback grounded in tool-based reasoning to guide and constrain route generation. We rigorously evaluate LARC on a carefully curated set of 48 constrained retrosynthesis planning tasks across 3 constraint types. LARC achieves a 72.9% success rate on these tasks, vastly outperforming LLM baselines and approaching human expert-level success in substantially less time. The LARC framework is extensible, and serves as a first step towards an effective agentic tool or a co-scientist to human experts for constrained retrosynthesis.