Conspectus Recent advances in computer hardware and software have led to a revolution in deep neural networks that has impacted fields ranging from language translation to computer vision. Deep ...learning has also impacted a number of areas in drug discovery, including the analysis of cellular images and the design of novel routes for the synthesis of organic molecules. While work in these areas has been impactful, a complete review of the applications of deep learning in drug discovery would be beyond the scope of a single Account. In this Account, we will focus on two key areas where deep learning has impacted molecular design: the prediction of molecular properties and the de novo generation of suggestions for new molecules. One of the most significant advances in the development of quantitative structure–activity relationships (QSARs) has come from the application of deep learning methods to the prediction of the biological activity and physical properties of molecules in drug discovery programs. Rather than employing the expert-derived chemical features typically used to build predictive models, researchers are now using deep learning to develop novel molecular representations. These representations, coupled with the ability of deep neural networks to uncover complex, nonlinear relationships, have led to state-of-the-art performance. While deep learning has changed the way that many researchers approach QSARs, it is not a panacea. As with any other machine learning task, the design of predictive models is dependent on the quality, quantity, and relevance of available data. Seemingly fundamental issues, such as optimal methods for creating a training set, are still open questions for the field. Another critical area that is still the subject of multiple research efforts is the development of methods for assessing the confidence in a model. Deep learning has also contributed to a renaissance in the application of de novo molecule generation. Rather than relying on manually defined heuristics, deep learning methods learn to generate new molecules based on sets of existing molecules. Techniques that were originally developed for areas such as image generation and language translation have been adapted to the generation of molecules. These deep learning methods have been coupled with the predictive models described above and are being used to generate new molecules with specific predicted biological activity profiles. While these generative algorithms appear promising, there have been only a few reports on the synthesis and testing of molecules based on designs proposed by generative models. The evaluation of the diversity, quality, and ultimate value of molecules produced by generative models is still an open question. While the field has produced a number of benchmarks, it has yet to agree on how one should ultimately assess molecules “invented” by an algorithm.
Uncertainty quantification (UQ) is an important component of molecular property prediction, particularly for drug discovery applications where model predictions direct experimental design and where ...unanticipated imprecision wastes valuable time and resources. The need for UQ is especially acute for neural models, which are becoming increasingly standard yet are challenging to interpret. While several approaches to UQ have been proposed in the literature, there is no clear consensus on the comparative performance of these models. In this paper, we study this question in the context of regression tasks. We systematically evaluate several methods on five regression data sets using multiple complementary performance metrics. Our experiments show that none of the methods we tested is unequivocally superior to all others, and none produces a particularly reliable ranking of errors across multiple data sets. While we believe that these results show that existing UQ methods are not sufficient for all common use cases and further research is needed, we conclude with a practical recommendation as to which existing techniques seem to perform well relative to others.
Development of new products often relies on the discovery of novel molecules. While conventional molecular design involves using human expertise to propose, synthesize, and test new molecules, this ...process can be cost and time intensive, limiting the number of molecules that can be reasonably tested. Generative modeling provides an alternative approach to molecular discovery by reformulating molecular design as an inverse design problem. Here, we review the recent advances in the state‐of‐the‐art of generative molecular design and discusses the considerations for integrating these models into real molecular discovery campaigns. We first review the model design choices required to develop and train a generative model including common 1D, 2D, and 3D representations of molecules and typical generative modeling neural network architectures. We then describe different problem statements for molecular discovery applications and explore the benchmarks used to evaluate models based on those problem statements. Finally, we discuss the important factors that play a role in integrating generative models into experimental workflows. Our aim is that this review will equip the reader with the information and context necessary to utilize generative modeling within their domain.
This article is categorized under:
Data Science > Artificial Intelligence/Machine Learning
Generative modeling approaches can be used to discover novel and diverse compounds.
Modeling Local Coherence: An Entity-Based Approach Barzilay, Regina; Lapata, Mirella
Computational linguistics - Association for Computational Linguistics,
03/2008, Letnik:
34, Številka:
1
Journal Article
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This article proposes a novel framework for representing and measuring local coherence. Central to this approach is the entity-grid representation of discourse, which captures patterns of entity ...distribution in a text. The algorithm introduced in the article automatically abstracts a text into a set of entity transition sequences and records distributional, syntactic, and referential information about discourse entities. We re-conceptualize coherence assessment as a learning task and show that our entity-based representation is well-suited for ranking-based generation and text classification tasks. Using the proposed representation, we achieve good performance on text ordering, summary coherence evaluation, and readability assessment.
Advancements in neural machinery have led to a wide range of algorithmic solutions for molecular property prediction. Two classes of models in particular have yielded promising results: neural ...networks applied to computed molecular fingerprints or expert-crafted descriptors and graph convolutional neural networks that construct a learned molecular representation by operating on the graph structure of the molecule. However, recent literature has yet to clearly determine which of these two methods is superior when generalizing to new chemical space. Furthermore, prior research has rarely examined these new models in industry research settings in comparison to existing employed models. In this paper, we benchmark models extensively on 19 public and 16 proprietary industrial data sets spanning a wide variety of chemical end points. In addition, we introduce a graph convolutional model that consistently matches or outperforms models using fixed molecular descriptors as well as previous graph neural architectures on both public and proprietary data sets. Our empirical findings indicate that while approaches based on these representations have yet to reach the level of experimental reproducibility, our proposed model nevertheless offers significant improvements over models currently used in industrial workflows.
The task of learning an expressive molecular representation is central to developing quantitative structure–activity and property relationships. Traditional approaches rely on group additivity rules, ...empirical measurements or parameters, or generation of thousands of descriptors. In this paper, we employ a convolutional neural network for this embedding task by treating molecules as undirected graphs with attributed nodes and edges. Simple atom and bond attributes are used to construct atom-specific feature vectors that take into account the local chemical environment using different neighborhood radii. By working directly with the full molecular graph, there is a greater opportunity for models to identify important features relevant to a prediction task. Unlike other graph-based approaches, our atom featurization preserves molecule-level spatial information that significantly enhances model performance. Our models learn to identify important features of atom clusters for the prediction of aqueous solubility, octanol solubility, melting point, and toxicity. Extensions and limitations of this strategy are discussed.
We present a supervised learning approach to predict the products of organic reactions given their reactants, reagents, and solvent(s). The prediction task is factored into two stages comparable to ...manual expert approaches: considering possible sites of reactivity and evaluating their relative likelihoods. By training on hundreds of thousands of reaction precedents covering a broad range of reaction types from the patent literature, the neural model makes informed predictions of chemical reactivity. The model predicts the major product correctly over 85% of the time requiring around 100 ms per example, a significantly higher accuracy than achieved by previous machine learning approaches, and performs on par with expert chemists with years of formal training. We gain additional insight into predictions
the design of the neural model, revealing an understanding of chemistry qualitatively consistent with manual approaches.
Due to the rapid emergence of antibiotic-resistant bacteria, there is a growing need to discover new antibiotics. To address this challenge, we trained a deep neural network capable of predicting ...molecules with antibacterial activity. We performed predictions on multiple chemical libraries and discovered a molecule from the Drug Repurposing Hub—halicin—that is structurally divergent from conventional antibiotics and displays bactericidal activity against a wide phylogenetic spectrum of pathogens including Mycobacterium tuberculosis and carbapenem-resistant Enterobacteriaceae. Halicin also effectively treated Clostridioides difficile and pan-resistant Acinetobacter baumannii infections in murine models. Additionally, from a discrete set of 23 empirically tested predictions from >107 million molecules curated from the ZINC15 database, our model identified eight antibacterial compounds that are structurally distant from known antibiotics. This work highlights the utility of deep learning approaches to expand our antibiotic arsenal through the discovery of structurally distinct antibacterial molecules.
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•A deep learning model is trained to predict antibiotics based on structure•Halicin is predicted as an antibacterial molecule from the Drug Repurposing Hub•Halicin shows broad-spectrum antibiotic activities in mice•More antibiotics with distinct structures are predicted from the ZINC15 database
A trained deep neural network predicts antibiotic activity in molecules that are structurally different from known antibiotics, among which Halicin exhibits efficacy against broad-spectrum bacterial infections in mice.
Computer assistance in synthesis design has existed for over 40 years, yet retrosynthesis planning software has struggled to achieve widespread adoption. One critical challenge in developing ...high-quality pathway suggestions is that proposed reaction steps often fail when attempted in the laboratory, despite initially seeming viable. The true measure of success for any synthesis program is whether the predicted outcome matches what is observed experimentally. We report a model framework for anticipating reaction outcomes that combines the traditional use of reaction templates with the flexibility in pattern recognition afforded by neural networks. Using 15 000 experimental reaction records from granted United States patents, a model is trained to select the major (recorded) product by ranking a self-generated list of candidates where one candidate is known to be the major product. Candidate reactions are represented using a unique edit-based representation that emphasizes the fundamental transformation from reactants to products, rather than the constituent molecules’ overall structures. In a 5-fold cross-validation, the trained model assigns the major product rank 1 in 71.8% of cases, rank ≤3 in 86.7% of cases, and rank ≤5 in 90.8% of cases.
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