John Bradshaw

Joonyoung F. Joung, Mun Hong Fong, Jihye Roh et al.

Mechanistic understanding of organic reactions can facilitate reaction development, impurity prediction, and in principle, reaction discovery. While several machine learning models have sought to address the task of predicting reaction products, their extension to predicting reaction mechanisms has been impeded by the lack of a corresponding mechanistic dataset. In this study, we construct such a dataset by imputing intermediates between experimentally reported reactants and products using expert reaction templates and train several machine learning models on the resulting dataset of 5,184,184 elementary steps. We explore the performance and capabilities of these models, focusing on their ability to predict reaction pathways and recapitulate the roles of catalysts and reagents. Additionally, we demonstrate the potential of mechanistic models in predicting impurities, often overlooked by conventional models. We conclude by evaluating the generalizability of mechanistic models to new reaction types, revealing challenges related to dataset diversity, consecutive predictions, and violations of atom conservation.

John Bradshaw, Brooks Paige, Matt J. Kusner et al.

When designing new molecules with particular properties, it is not only important what to make but crucially how to make it. These instructions form a synthesis directed acyclic graph (DAG), describing how a large vocabulary of simple building blocks can be recursively combined through chemical reactions to create more complicated molecules of interest. In contrast, many current deep generative models for molecules ignore synthesizability. We therefore propose a deep generative model that better represents the real world process, by directly outputting molecule synthesis DAGs. We argue that this provides sensible inductive biases, ensuring that our model searches over the same chemical space that chemists would also have access to, as well as interpretability. We show that our approach is able to model chemical space well, producing a wide range of diverse molecules, and allows for unconstrained optimization of an inherently constrained problem: maximize certain chemical properties such that discovered molecules are synthesizable.

John Bradshaw, Brooks Paige, Matt J. Kusner et al.

Deep generative models are able to suggest new organic molecules by generating strings, trees, and graphs representing their structure. While such models allow one to generate molecules with desirable properties, they give no guarantees that the molecules can actually be synthesized in practice. We propose a new molecule generation model, mirroring a more realistic real-world process, where (a) reactants are selected, and (b) combined to form more complex molecules. More specifically, our generative model proposes a bag of initial reactants (selected from a pool of commercially-available molecules) and uses a reaction model to predict how they react together to generate new molecules. We first show that the model can generate diverse, valid and unique molecules due to the useful inductive biases of modeling reactions. Furthermore, our model allows chemists to interrogate not only the properties of the generated molecules but also the feasibility of the synthesis routes. We conclude by using our model to solve retrosynthesis problems, predicting a set of reactants that can produce a target product.

John Bradshaw, Matt J. Kusner, Brooks Paige et al.

Chemical reactions can be described as the stepwise redistribution of electrons in molecules. As such, reactions are often depicted using `arrow-pushing' diagrams which show this movement as a sequence of arrows. We propose an electron path prediction model (ELECTRO) to learn these sequences directly from raw reaction data. Instead of predicting product molecules directly from reactant molecules in one shot, learning a model of electron movement has the benefits of (a) being easy for chemists to interpret, (b) incorporating constraints of chemistry, such as balanced atom counts before and after the reaction, and (c) naturally encoding the sparsity of chemical reactions, which usually involve changes in only a small number of atoms in the reactants.We design a method to extract approximate reaction paths from any dataset of atom-mapped reaction SMILES strings. Our model achieves excellent performance on an important subset of the USPTO reaction dataset, comparing favorably to the strongest baselines. Furthermore, we show that our model recovers a basic knowledge of chemistry without being explicitly trained to do so.

John Bradshaw, Alexander G. de G. Matthews, Zoubin Ghahramani

Deep neural networks (DNNs) have excellent representative power and are state of the art classifiers on many tasks. However, they often do not capture their own uncertainties well making them less robust in the real world as they overconfidently extrapolate and do not notice domain shift. Gaussian processes (GPs) with RBF kernels on the other hand have better calibrated uncertainties and do not overconfidently extrapolate far from data in their training set. However, GPs have poor representational power and do not perform as well as DNNs on complex domains. In this paper we show that GP hybrid deep networks, GPDNNs, (GPs on top of DNNs and trained end-to-end) inherit the nice properties of both GPs and DNNs and are much more robust to adversarial examples. When extrapolating to adversarial examples and testing in domain shift settings, GPDNNs frequently output high entropy class probabilities corresponding to essentially "don't know". GPDNNs are therefore promising as deep architectures that know when they don't know.