We devise an approach for targeted molecular design, a problem of interest in computational drug discovery: given a target protein site, we wish to generate a chemical with both high binding affinity to the target and satisfactory pharmacological properties. This problem is made difficult by the enormity and discreteness of the space of potential therapeutics, as well as the graph-structured nature of biomolecular surface sites. Using a dataset of protein-ligand complexes, we surmount these issues by extracting a signature of the target site with a graph convolutional network and by encoding the discrete chemical into a continuous latent vector space. The latter embedding permits gradient-based optimization in molecular space, which we perform using learned differentiable models of binding affinity and other pharmacological properties. We show that our approach is able to efficiently optimize these multiple objectives and discover new molecules with potentially useful binding properties, validated via docking methods.
@cite_67: 
@cite_64: Computational medicinal chemistry offers viable strategies for finding, characterizing, and optimizing innovative pharmacologically active compounds. Technological advances in both computer hardware and software as well as biological chemistry have enabled a renaissance of computer-assisted “de novo” design of molecules with desired pharmacological properties. Here, we present our current perspective on the concept of automated molecule generation by highlighting chemocentric methods that may capture druglike chemical space, consider ligand promiscuity for hit and lead finding, and provide fresh ideas for the rational design of customized screening of compound libraries.
@cite_37: Automatic Chemical Design leverages recent advances in deep generative modelling to provide a framework for performing continuous optimization of molecular properties. Although the provision of a continuous representation for prospective lead drug candidates has opened the door to hitherto inaccessible tools of mathematical optimization, some challenges remain for the design process. One known pathology is the model's tendency to decode invalid molecular structures. The goal of this thesis is to test the hypothesis that the origin of this pathology is rooted in the current formulation of Bayesian optimization. Recasting the optimization procedure as a constrained Bayesian optimization problem results in novel drug compounds produced by the model consistently ranking in the 100th percentile of the distribution over training set scores.
@cite_8: Deep generative models have been enjoying success in modeling continuous data. However it remains challenging to capture the representations for discrete structures with formal grammars and semantics, e.g., computer programs and molecular structures. How to generate both syntactically and semantically correct data still remains largely an open problem. Inspired by the theory of compiler where the syntax and semantics check is done via syntax-directed translation (SDT), we propose a novel syntax-directed variational autoencoder (SD-VAE) by introducing stochastic lazy attributes. This approach converts the offline SDT check into on-the-fly generated guidance for constraining the decoder. Comparing to the state-of-the-art methods, our approach enforces constraints on the output space so that the output will be not only syntactically valid, but also semantically reasonable. We evaluate the proposed model with applications in programming language and molecules, including reconstruction and program molecule optimization. The results demonstrate the effectiveness in incorporating syntactic and semantic constraints in discrete generative models, which is significantly better than current state-of-the-art approaches.
@cite_41: Deep generative models have been wildly successful at learning coherent latent representations for continuous data such as video and audio. However, generative modeling of discrete data such as arithmetic expressions and molecular structures still poses significant challenges. Crucially, state-of-the-art methods often produce outputs that are not valid. We make the key observation that frequently, discrete data can be represented as a parse tree from a context-free grammar. We propose a variational autoencoder which encodes and decodes directly to and from these parse trees, ensuring the generated outputs are always valid. Surprisingly, we show that not only does our model more often generate valid outputs, it also learns a more coherent latent space in which nearby points decode to similar discrete outputs. We demonstrate the effectiveness of our learned models by showing their improved performance in Bayesian optimization for symbolic regression and molecular synthesis.
@cite_23: We seek to automate the design of molecules based on specific chemical properties. In computational terms, this task involves continuous embedding and generation of molecular graphs. Our primary contribution is the direct realization of molecular graphs, a task previously approached by generating linear SMILES strings instead of graphs. Our junction tree variational autoencoder generates molecular graphs in two phases, by first generating a tree-structured scaffold over chemical substructures, and then combining them into a molecule with a graph message passing network. This approach allows us to incrementally expand molecules while maintaining chemical validity at every step. We evaluate our model on multiple tasks ranging from molecular generation to optimization. Across these tasks, our model outperforms previous state-of-the-art baselines by a significant margin.
@cite_5: Artificial neural networks had their first heyday in molecular informatics and drug discovery approximately two decades ago. Currently, we are witnessing renewed interest in adapting advanced neural network architectures for pharmaceutical research by borrowing from the field of “deep learning”. Compared with some of the other life sciences, their application in drug discovery is still limited. Here, we provide an overview of this emerging field of molecular informatics, present the basic concepts of prominent deep learning methods and offer motivation to explore these techniques for their usefulness in computer-assisted drug discovery and design. We specifically emphasize deep neural networks, restricted Boltzmann machine networks and convolutional networks.
@cite_11: This paper proposes a general method for improving the structure and quality of sequences generated by a recurrent neural network (RNN), while maintaining information originally learned from data, as well as sample diversity. An RNN is first pre-trained on data using maximum likelihood estimation (MLE), and the probability distribution over the next token in the sequence learned by this model is treated as a prior policy. Another RNN is then trained using reinforcement learning (RL) to generate higher-quality outputs that account for domain-specific incentives while retaining proximity to the prior policy of the MLE RNN. To formalize this objective, we derive novel off-policy RL methods for RNNs from KL-control. The effectiveness of the approach is demonstrated on two applications; 1) generating novel musical melodies, and 2) computational molecular generation. For both problems, we show that the proposed method improves the desired properties and structure of the generated sequences, while maintaining information learned from data.
Given the importance of chemical design to the pharmaceutical development process, a considerable body of work has been devoted to computational methods for improving it (e.g. @cite_5 @cite_64 ). Much recent research on constructing continuous embeddings of chemicals has used Bayesian optimization to generate molecules with desirable properties @cite_67 @cite_8 @cite_23 @cite_41 @cite_11 @cite_37 . However, these methods do not perform chemical design, aimed at a particular molecule of interest.