AMPL: A Data-Driven Modeling Pipeline for Drug Discovery

One of the key requirements for incorporating machine learning into the drug discovery process is complete reproducibility and traceability of the model building and evaluation process. With this in mind, we have developed an end-to-end modular and extensible software pipeline for building and sharing machine learning models that predict key pharma-relevant parameters. The ATOM Modeling PipeLine, or AMPL, extends the functionality of the open source library DeepChem and supports an array of machine learning and molecular featurization tools. We have benchmarked AMPL on a large collection of pharmaceutical datasets covering a wide range of parameters. As a result of these comprehensive experiments, we have found that physicochemical descriptors and deep learning-based graph representations significantly outperform traditional fingerprints in the characterization of molecular features. We have also found that dataset size is directly correlated to prediction performance, and that single-task deep learning models only outperform shallow learners if there is sufficient data. Likewise, dataset size has a direct impact on model predictivity, independent of comprehensive hyperparameter model tuning. Our findings point to the need for public dataset integration or multi-task/transfer learning approaches. Lastly, we found that uncertainty quantification (UQ) analysis may help identify model error; however, efficacy of UQ to filter predictions varies considerably between datasets and featurization/model types. AMPL is open source and available for download at http://github.com/ATOMconsortium/AMPL.

MoleculeNet: A Benchmark for Molecular Machine Learning

Molecular machine learning has been maturing rapidly over the last few years. Improved methods and the presence of larger datasets have enabled machine learning algorithms to make increasingly accurate predictions about molecular properties. However, algorithmic progress has been limited due to the lack of a standard benchmark to compare the efficacy of proposed methods; most new algorithms are benchmarked on different datasets making it challenging to gauge the quality of proposed methods. This work introduces MoleculeNet, a large scale benchmark for molecular machine learning. MoleculeNet curates multiple public datasets, establishes metrics for evaluation, and offers high quality open-source implementations of multiple previously proposed molecular featurization and learning algorithms (released as part of the DeepChem open source library). MoleculeNet benchmarks demonstrate that learnable representations are powerful tools for molecular machine learning and broadly offer the best performance. However, this result comes with caveats. Learnable representations still struggle to deal with complex tasks under data scarcity and highly imbalanced classification. For quantum mechanical and biophysical datasets, the use of physics-aware featurizations can be more important than choice of particular learning algorithm.

PotentialNet for Molecular Property Prediction

The arc of drug discovery entails a multiparameter optimization problem spanning vast length scales. They key parameters range from solubility (angstroms) to protein-ligand binding (nanometers) to in vivo toxicity (meters). Through feature learning---instead of feature engineering---deep neural networks promise to outperform both traditional physics-based and knowledge-based machine learning models for predicting molecular properties pertinent to drug discovery. To this end, we present the PotentialNet family of graph convolutions. These models are specifically designed for and achieve state-of-the-art performance for protein-ligand binding affinity. We further validate these deep neural networks by setting new standards of performance in several ligand-based tasks. In parallel, we introduce a new metric, the Regression Enrichment Factor $EF_\chi^{(R)}$, to measure the early enrichment of computational models for chemical data. Finally, we introduce a cross-validation strategy based on structural homology clustering that can more accurately measure model generalizability, which crucially distinguishes the aims of machine learning for drug discovery from standard machine learning tasks.

Retrosynthetic reaction prediction using neural sequence-to-sequence models

We describe a fully data driven model that learns to perform a retrosynthetic reaction prediction task, which is treated as a sequence-to-sequence mapping problem. The end-to-end trained model has an encoder-decoder architecture that consists of two recurrent neural networks, which has previously shown great success in solving other sequence-to-sequence prediction tasks such as machine translation. The model is trained on 50,000 experimental reaction examples from the United States patent literature, which span 10 broad reaction types that are commonly used by medicinal chemists. We find that our model performs comparably with a rule-based expert system baseline model, and also overcomes certain limitations associated with rule-based expert systems and with any machine learning approach that contains a rule-based expert system component. Our model provides an important first step towards solving the challenging problem of computational retrosynthetic analysis.

Atomic Convolutional Networks for Predicting Protein-Ligand Binding Affinity

Empirical scoring functions based on either molecular force fields or cheminformatics descriptors are widely used, in conjunction with molecular docking, during the early stages of drug discovery to predict potency and binding affinity of a drug-like molecule to a given target. These models require expert-level knowledge of physical chemistry and biology to be encoded as hand-tuned parameters or features rather than allowing the underlying model to select features in a data-driven procedure. Here, we develop a general 3-dimensional spatial convolution operation for learning atomic-level chemical interactions directly from atomic coordinates and demonstrate its application to structure-based bioactivity prediction. The atomic convolutional neural network is trained to predict the experimentally determined binding affinity of a protein-ligand complex by direct calculation of the energy associated with the complex, protein, and ligand given the crystal structure of the binding pose. Non-covalent interactions present in the complex that are absent in the protein-ligand sub-structures are identified and the model learns the interaction strength associated with these features. We test our model by predicting the binding free energy of a subset of protein-ligand complexes found in the PDBBind dataset and compare with state-of-the-art cheminformatics and machine learning-based approaches. We find that all methods achieve experimental accuracy and that atomic convolutional networks either outperform or perform competitively with the cheminformatics based methods. Unlike all previous protein-ligand prediction systems, atomic convolutional networks are end-to-end and fully-differentiable. They represent a new data-driven, physics-based deep learning model paradigm that offers a strong foundation for future improvements in structure-based bioactivity prediction.

Low Data Drug Discovery with One-shot Learning

Recent advances in machine learning have made significant contributions to drug discovery. Deep neural networks in particular have been demonstrated to provide significant boosts in predictive power when inferring the properties and activities of small-molecule compounds. However, the applicability of these techniques has been limited by the requirement for large amounts of training data. In this work, we demonstrate how one-shot learning can be used to significantly lower the amounts of data required to make meaningful predictions in drug discovery applications. We introduce a new architecture, the residual LSTM embedding, that, when combined with graph convolutional neural networks, significantly improves the ability to learn meaningful distance metrics over small-molecules. We open source all models introduced in this work as part of DeepChem, an open-source framework for deep-learning in drug discovery.

Learning Protein Dynamics with Metastable Switching Systems

We introduce a machine learning approach for extracting fine-grained representations of protein evolution from molecular dynamics datasets. Metastable switching linear dynamical systems extend standard switching models with a physically-inspired stability constraint. This constraint enables the learning of nuanced representations of protein dynamics that closely match physical reality. We derive an EM algorithm for learning, where the E-step extends the forward-backward algorithm for HMMs and the M-step requires the solution of large biconvex optimization problems. We construct an approximate semidefinite program solver based on the Frank-Wolfe algorithm and use it to solve the M-step. We apply our EM algorithm to learn accurate dynamics from large simulation datasets for the opioid peptide met-enkephalin and the proto-oncogene Src-kinase. Our learned models demonstrate significant improvements in temporal coherence over HMMs and standard switching models for met-enkephalin, and sample transition paths (possibly useful in rational drug design) for Src-kinase.

Massively Multitask Networks for Drug Discovery

Massively multitask neural architectures provide a learning framework for drug discovery that synthesizes information from many distinct biological sources. To train these architectures at scale, we gather large amounts of data from public sources to create a dataset of nearly 40 million measurements across more than 200 biological targets. We investigate several aspects of the multitask framework by performing a series of empirical studies and obtain some interesting results: (1) massively multitask networks obtain predictive accuracies significantly better than single-task methods, (2) the predictive power of multitask networks improves as additional tasks and data are added, (3) the total amount of data and the total number of tasks both contribute significantly to multitask improvement, and (4) multitask networks afford limited transferability to tasks not in the training set. Our results underscore the need for greater data sharing and further algorithmic innovation to accelerate the drug discovery process.

Understanding Protein Dynamics with L1-Regularized Reversible Hidden Markov Models

We present a machine learning framework for modeling protein dynamics. Our approach uses L1-regularized, reversible hidden Markov models to understand large protein datasets generated via molecular dynamics simulations. Our model is motivated by three design principles: (1) the requirement of massive scalability; (2) the need to adhere to relevant physical law; and (3) the necessity of providing accessible interpretations, critical for both cellular biology and rational drug design. We present an EM algorithm for learning and introduce a model selection criteria based on the physical notion of convergence in relaxation timescales. We contrast our model with standard methods in biophysics and demonstrate improved robustness. We implement our algorithm on GPUs and apply the method to two large protein simulation datasets generated respectively on the NCSA Bluewaters supercomputer and the Folding@Home distributed computing network. Our analysis identifies the conformational dynamics of the ubiquitin protein critical to cellular signaling, and elucidates the stepwise activation mechanism of the c-Src kinase protein.

The Extended Parameter Filter

The parameters of temporal models, such as dynamic Bayesian networks, may be modelled in a Bayesian context as static or atemporal variables that influence transition probabilities at every time step. Particle filters fail for models that include such variables, while methods that use Gibbs sampling of parameter variables may incur a per-sample cost that grows linearly with the length of the observation sequence. Storvik devised a method for incremental computation of exact sufficient statistics that, for some cases, reduces the per-sample cost to a constant. In this paper, we demonstrate a connection between Storvik's filter and a Kalman filter in parameter space and establish more general conditions under which Storvik's filter works. Drawing on an analogy to the extended Kalman filter, we develop and analyze, both theoretically and experimentally, a Taylor approximation to the parameter posterior that allows Storvik's method to be applied to a broader class of models. Our experiments on both synthetic examples and real applications show improvement over existing methods.