Samuel Genheden

Yujia Guo, Mikhail Kabeshov, Tat Hong Duong Le et al.

Selecting efficient multi-step synthetic routes is a central challenge in organic synthesis, particularly in medicinal and process chemistry, where route choice directly impacts feasibility, cost, and development efficiency. Data-driven assessment systems often oversimplify the multi-objective nature of synthesis design and rely on proxy datasets, such as patent routes, rather than universally grounded criteria. To address this, we introduce an expert-augmented, data-driven scoring framework that integrates machine learning with chemists' domain knowledge for both numerical and explainable route assessment. A DeepSets-based model is trained using tree edit distance between reference and machine-generated routes, and then fine-tuned with expert evaluations to produce both quantitative scores and interpretable qualitative categories: Good, Plausible, and Bad. The resulting system achieves a Spearman correlation coefficient of 0.78 and a Pearson correlation of 0.77 for category assessment prediction, and 60.2% top-1 ranking accuracy for score prediction, substantially outperforming the previous baseline of 17.5%.

Paula Torren-Peraire, Alan Kai Hassen, Samuel Genheden et al.

Retrosynthesis consists of breaking down a chemical compound recursively step-by-step into molecular precursors until a set of commercially available molecules is found with the goal to provide a synthesis route. Its two primary research directions, single-step retrosynthesis prediction, which models the chemical reaction logic, and multi-step synthesis planning, which tries to find the correct sequence of reactions, are inherently intertwined. Still, this connection is not reflected in contemporary research. In this work, we combine these two major research directions by applying multiple single-step retrosynthesis models within multi-step synthesis planning and analyzing their impact using public and proprietary reaction data. We find a disconnection between high single-step performance and potential route-finding success, suggesting that single-step models must be evaluated within synthesis planning in the future. Furthermore, we show that the commonly used single-step retrosynthesis benchmark dataset USPTO-50k is insufficient as this evaluation task does not represent model performance and scalability on larger and more diverse datasets. For multi-step synthesis planning, we show that the choice of the single-step model can improve the overall success rate of synthesis planning by up to +28% compared to the commonly used baseline model. Finally, we show that each single-step model finds unique synthesis routes, and differs in aspects such as route-finding success, the number of found synthesis routes, and chemical validity, making the combination of single-step retrosynthesis prediction and multi-step synthesis planning a crucial aspect when developing future methods.

Alan Kai Hassen, Paula Torren-Peraire, Samuel Genheden et al.

Retrosynthesis is the task of breaking down a chemical compound recursively step-by-step into molecular precursors until a set of commercially available molecules is found. Consequently, the goal is to provide a valid synthesis route for a molecule. As more single-step models develop, we see increasing accuracy in the prediction of molecular disconnections, potentially improving the creation of synthetic paths. Multi-step approaches repeatedly apply the chemical information stored in single-step retrosynthesis models. However, this connection is not reflected in contemporary research, fixing either the single-step model or the multi-step algorithm in the process. In this work, we establish a bridge between both tasks by benchmarking the performance and transfer of different single-step retrosynthesis models to the multi-step domain by leveraging two common search algorithms, Monte Carlo Tree Search and Retro*. We show that models designed for single-step retrosynthesis, when extended to multi-step, can have a tremendous impact on the route finding capabilities of current multi-step methods, improving performance by up to +30% compared to the most widely used model. Furthermore, we observe no clear link between contemporary single-step and multi-step evaluation metrics, showing that single-step models need to be developed and tested for the multi-step domain and not as an isolated task to find synthesis routes for molecules of interest.

Laura van Weesep, Samuel Genheden, Ola Engkvist et al.

Large-language models (LLMs) and agentic systems present exciting opportunities to accelerate drug discovery. In this study, we examine the modularity of LLM-based agentic systems for drug discovery, i.e., whether parts of the system such as the LLM and type of agent are interchangeable, a topic that has received limited attention in drug discovery. We compare the performance of different LLMs and the effectiveness of tool-calling agents versus code-generating agents. Our case study, comparing performance in orchestrating tools for chemistry and drug discovery using an LLM-as-a-judge score, shows that Claude-3.5-Sonnet, Claude-3.7-Sonnet and GPT-4o outperform alternative language models such as Llama-3.1-8B, Llama-3.1-70B, GPT-3.5-Turbo, and Nova-Micro. Although we confirm that code-generating agents outperform the tool-calling ones on average, we show that this is highly question- and model-dependent. Furthermore, the impact of replacing system prompts is dependent on the question and model, underscoring that even in this particular domain one cannot just replace components of the system without re-engineering. Our study highlights the necessity of further research into the modularity of agentic systems to enable the development of reliable and modular solutions for real-world problems.