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.

Applications of Deep Learning in Molecule Generation and Molecular Property Prediction.

Structure-based virtual screening is an important tool in early stage drug discovery that scores the interactions between a target protein and candidate ligands. As virtual libraries continue to grow (in excess of $10^8$ molecules), so too do the resources necessary to conduct exhaustive virtual screening campaigns on these libraries. However, Bayesian optimization techniques can aid in their exploration: a surrogate structure-property relationship model trained on the predicted affinities of a subset of the library can be applied to the remaining library members, allowing the least promising compounds to be excluded from evaluation. In this study, we assess various surrogate model architectures, acquisition functions, and acquisition batch sizes as applied to several protein-ligand docking datasets and observe significant reductions in computational costs, even when using a greedy acquisition strategy; for example, 87.9% of the top-50000 ligands can be found after testing only 2.4% of a 100M member library. Such model-guided searches mitigate the increasing computational costs of screening increasingly large virtual libraries and can accelerate high-throughput virtual screening campaigns with applications beyond docking.

/pdf/accelerating-high-throughput-virtual-screening-through-39rb4i2cxb.pdf

Accelerating high-throughput virtual screening through molecular pool-based active learning

Alchemical free energy calculations are a useful tool for predicting free energy differences associated with the transfer of molecules from one environment to another. The hallmark of these methods is the use of "bridging" potential energy functions representing alchemical intermediate states that cannot exist as real chemical species. The data collected from these bridging alchemical thermodynamic states allows the efficient computation of transfer free energies (or differences in transfer free energies) with orders of magnitude less simulation time than simulating the transfer process directly. While these methods are highly flexible, care must be taken in avoiding common pitfalls to ensure that computed free energy differences can be robust and reproducible for the chosen force field, and that appropriate corrections are included to permit direct comparison with experimental data. In this paper, we review current best practices for several popular application domains of alchemical free energy calculations performed with equilibrium simulations, in particular relative and absolute small molecule binding free energy calculations to biomolecular targets.

Best Practices for Alchemical Free Energy Calculations [Article v1.0].

With the advent of make-on-demand commercial libraries, the number of purchasable compounds available for virtual screening and assay has grown explosively in recent years, with several libraries eclipsing one billion compounds. Today's screening libraries are larger and more diverse, enabling the discovery of more-potent hit compounds and unlocking new areas of chemical space, represented by new core scaffolds. Applying physics-based in silico screening methods in an exhaustive manner, where every molecule in the library must be enumerated and evaluated independently, is increasingly cost-prohibitive. Here, we introduce a protocol for machine learning-enhanced molecular docking based on active learning to dramatically increase throughput over traditional docking. We leverage a novel selection protocol that strikes a balance between two objectives: (1) identifying the best scoring compounds and (2) exploring a large region of chemical space, demonstrating superior performance compared to a purely greedy approach. Together with automated redocking of the top compounds, this method captures almost all the high scoring scaffolds in the library found by exhaustive docking. This protocol is applied to our recent virtual screening campaigns against the D4 and AMPC targets that produced dozens of highly potent, novel inhibitors, and a blind test against the MT1 target. Our protocol recovers more than 80% of the experimentally confirmed hits with a 14-fold reduction in compute cost, and more than 90% of the hit scaffolds in the top 5% of model predictions, preserving the diversity of the experimentally confirmed hit compounds.

/pdf/efficient-exploration-of-chemical-space-with-docking-and-1yivknib3o.pdf

Efficient Exploration of Chemical Space with Docking and Deep Learning.

There is a renewed interest in computer-aided synthesis planning, where the vast majority of approaches require the application of retrosynthetic reaction templates. Here we introduce RDChiral, an open-source Python wrapper for RDKit designed to provide consistent handling of stereochemical information in applying retrosynthetic transformations encoded as SMARTS strings. RDChiral is designed to enforce the introduction, destruction, retention, and inversion of chiral tetrahedral centers as well as the cis/trans configuration of double bonds. We also introduce an open-source implementation of a retrosynthetic template extraction algorithm to generate SMARTS patterns from atom-mapped reaction SMILES strings. In this application note, we describe the implementation of these two pieces of code and illustrate their use through many examples.

RDChiral: An RDKit Wrapper for Handling Stereochemistry in Retrosynthetic Template Extraction and Application.

The hit-to-lead and lead optimization processes usually involve the design, synthesis, and profiling of thousands of analogs prior to clinical candidate nomination. A hit finding campaign may begin...

Reaction-Based Enumeration, Active Learning, and Free Energy Calculations To Rapidly Explore Synthetically Tractable Chemical Space and Optimize Potency of Cyclin-Dependent Kinase 2 Inhibitors.

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Reaction-Based Enumeration, Active Learning, and Free Energy Calculations To Rapidly Explore Synthetically Tractable Chemical Space and Optimize Potency of Cyclin-Dependent Kinase 2 Inhibitors.