Beam Enumeration: Probabilistic Explainability For Sample Efficient Self-conditioned Molecular Design

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 is the first method to jointly address explainability and sample efficiency for molecular design.

14 Examples of How LLMs Can Transform Materials Science and Chemistry: A Reflection on a Large Language Model Hackathon

Chemistry and materials science are complex. Recently, there have been great successes in addressing this complexity using data-driven or computational techniques. Yet, the necessity of input structured in very specific forms and the fact that there is an ever-growing number of tools creates usability and accessibility challenges. Coupled with the reality that much data in these disciplines is unstructured, the effectiveness of these tools is limited. Motivated by recent works that indicated that large language models (LLMs) might help address some of these issues, we organized a hackathon event on the applications of LLMs in chemistry, materials science, and beyond. This article chronicles the projects built as part of this hackathon. Participants employed LLMs for various applications, including predicting properties of molecules and materials, designing novel interfaces for tools, extracting knowledge from unstructured data, and developing new educational applications. The diverse topics and the fact that working prototypes could be generated in less than two days highlight that LLMs will profoundly impact the future of our fields. The rich collection of ideas and projects also indicates that the applications of LLMs are not limited to materials science and chemistry but offer potential benefits to a wide range of scientific disciplines.

Augmented Memory: Capitalizing on Experience Replay to Accelerate De Novo Molecular Design

Sample efficiency is a fundamental challenge in de novo molecular design. Ideally, molecular generative models should learn to satisfy a desired objective under minimal oracle evaluations (computational prediction or wet-lab experiment). This problem becomes more apparent when using oracles that can provide increased predictive accuracy but impose a significant cost. Consequently, these oracles cannot be directly optimized under a practical budget. Molecular generative models have shown remarkable sample efficiency when coupled with reinforcement learning, as demonstrated in the Practical Molecular Optimization (PMO) benchmark. Here, we propose a novel algorithm called Augmented Memory that combines data augmentation with experience replay. We show that scores obtained from oracle calls can be reused to update the model multiple times. We compare Augmented Memory to previously proposed algorithms and show significantly enhanced sample efficiency in an exploitation task and a drug discovery case study requiring both exploration and exploitation. Our method achieves a new state-of-the-art in the PMO benchmark which enforces a computational budget, outperforming the previous best performing method on 19/23 tasks.

ChemCrow: Augmenting large-language models with chemistry tools

Large-language models (LLMs) have recently shown strong performance in tasks across domains, but struggle with chemistry-related problems. Moreover, these models lack access to external knowledge sources, limiting their usefulness in scientific applications. In this study, we introduce ChemCrow, an LLM chemistry agent designed to accomplish tasks across organic synthesis, drug discovery, and materials design. By integrating 13 expert-designed tools, ChemCrow augments the LLM performance in chemistry, and new capabilities emerge. Our evaluation, including both LLM and expert human assessments, demonstrates ChemCrow's effectiveness in automating a diverse set of chemical tasks. Surprisingly, we find that GPT-4 as an evaluator cannot distinguish between clearly wrong GPT-4 completions and GPT-4 + ChemCrow performance. There is a significant risk of misuse of tools like ChemCrow and we discuss their potential harms. Employed responsibly, ChemCrow not only aids expert chemists and lowers barriers for non-experts, but also fosters scientific advancement by bridging the gap between experimental and computational chemistry.

GAUCHE: A Library for Gaussian Processes in Chemistry

We introduce GAUCHE, a library for GAUssian processes in CHEmistry. Gaussian processes have long been a cornerstone of probabilistic machine learning, affording particular advantages for uncertainty quantification and Bayesian optimisation. Extending Gaussian processes to chemical representations, however, is nontrivial, necessitating kernels defined over structured inputs such as graphs, strings and bit vectors. By defining such kernels in GAUCHE, we seek to open the door to powerful tools for uncertainty quantification and Bayesian optimisation in chemistry. Motivated by scenarios frequently encountered in experimental chemistry, we showcase applications for GAUCHE in molecular discovery and chemical reaction optimisation. The codebase is made available at https://github.com/leojklarner/gauche

SELFIES and the future of molecular string representations

Artificial intelligence (AI) and machine learning (ML) are expanding in popularity for broad applications to challenging tasks in chemistry and materials science. Examples include the prediction of properties, the discovery of new reaction pathways, or the design of new molecules. The machine needs to read and write fluently in a chemical language for each of these tasks. Strings are a common tool to represent molecular graphs, and the most popular molecular string representation, SMILES, has powered cheminformatics since the late 1980s. However, in the context of AI and ML in chemistry, SMILES has several shortcomings -- most pertinently, most combinations of symbols lead to invalid results with no valid chemical interpretation. To overcome this issue, a new language for molecules was introduced in 2020 that guarantees 100\% robustness: SELFIES (SELF-referencIng Embedded Strings). SELFIES has since simplified and enabled numerous new applications in chemistry. In this manuscript, we look to the future and discuss molecular string representations, along with their respective opportunities and challenges. We propose 16 concrete Future Projects for robust molecular representations. These involve the extension toward new chemical domains, exciting questions at the interface of AI and robust languages and interpretability for both humans and machines. We hope that these proposals will inspire several follow-up works exploiting the full potential of molecular string representations for the future of AI in chemistry and materials science.

Dataset Bias in the Natural Sciences: A Case Study in Chemical Reaction Prediction and Synthesis Design

Datasets in the Natural Sciences are often curated with the goal of aiding scientific understanding and hence may not always be in a form that facilitates the application of machine learning. In this paper, we identify three trends within the fields of chemical reaction prediction and synthesis design that require a change in direction. First, the manner in which reaction datasets are split into reactants and reagents encourages testing models in an unrealistically generous manner. Second, we highlight the prevalence of mislabelled data, and suggest that the focus should be on outlier removal rather than data fitting only. Lastly, we discuss the problem of reagent prediction, in addition to reactant prediction, in order to solve the full synthesis design problem, highlighting the mismatch between what machine learning solves and what a lab chemist would need. Our critiques are also relevant to the burgeoning field of using machine learning to accelerate progress in experimental Natural Sciences, where datasets are often split in a biased way, are highly noisy, and contextual variables that are not evident from the data strongly influence the outcome of experiments.

Unassisted Noise Reduction of Chemical Reaction Data Sets

Existing deep learning models applied to reaction prediction in organic chemistry can reach high levels of accuracy (> 90% for Natural Language Processing-based ones). With no chemical knowledge embedded than the information learnt from reaction data, the quality of the data sets plays a crucial role in the performance of the prediction models. While human curation is prohibitively expensive, the need for unaided approaches to remove chemically incorrect entries from existing data sets is essential to improve artificial intelligence models' performance in synthetic chemistry tasks. Here we propose a machine learning-based, unassisted approach to remove chemically wrong entries from chemical reaction collections. We applied this method to the collection of chemical reactions Pistachio and to an open data set, both extracted from USPTO (United States Patent Office) patents. Our results show an improved prediction quality for models trained on the cleaned and balanced data sets. For the retrosynthetic models, the round-trip accuracy metric grows by 13 percentage points and the value of the cumulative Jensen Shannon divergence decreases by 30% compared to its original record. The coverage remains high with 97%, and the value of the class-diversity is not affected by the cleaning. The proposed strategy is the first unassisted rule-free technique to address automatic noise reduction in chemical data sets.

Mapping the Space of Chemical Reactions Using Attention-Based Neural Networks

Organic reactions are usually assigned to classes containing reactions with similar reagents and mechanisms. Reaction classes facilitate the communication of complex concepts and efficient navigation through chemical reaction space. However, the classification process is a tedious task. It requires the identification of the corresponding reaction class template via annotation of the number of molecules in the reactions, the reaction center, and the distinction between reactants and reagents. This work shows that transformer-based models can infer reaction classes from non-annotated, simple text-based representations of chemical reactions. Our best model reaches a classification accuracy of 98.2%. We also show that the learned representations can be used as reaction fingerprints that capture fine-grained differences between reaction classes better than traditional reaction fingerprints. The insights into chemical reaction space enabled by our learned fingerprints are illustrated by an interactive reaction atlas providing visual clustering and similarity searching.

Exploring Chemical Space using Natural Language Processing Methodologies for Drug Discovery

Text-based representations of chemicals and proteins can be thought of as unstructured languages codified by humans to describe domain-specific knowledge. Advances in natural language processing (NLP) methodologies in the processing of spoken languages accelerated the application of NLP to elucidate hidden knowledge in textual representations of these biochemical entities and then use it to construct models to predict molecular properties or to design novel molecules. This review outlines the impact made by these advances on drug discovery and aims to further the dialogue between medicinal chemists and computer scientists.