Learning Multimodal Graph-to-Graph Translation for Molecular Optimization

We view molecular optimization as a graph-to-graph translation problem. The goal is to learn to map from one molecular graph to another with better properties based on an available corpus of paired molecules. Since molecules can be optimized in different ways, there are multiple viable translations for each input graph. A key challenge is therefore to model diverse translation outputs. Our primary contributions include a junction tree encoder-decoder for learning diverse graph translations along with a novel adversarial training method for aligning distributions of molecules. Diverse output distributions in our model are explicitly realized by low-dimensional latent vectors that modulate the translation process. We evaluate our model on multiple molecular optimization tasks and show that our model outperforms previous state-of-the-art baselines

Computer-Aided Multi-Objective Optimization in Small Molecule Discovery

Molecular discovery is a multi-objective optimization problem that requires identifying a molecule or set of molecules that balance multiple, often competing, properties. Multi-objective molecular design is commonly addressed by combining properties of interest into a single objective function using scalarization, which imposes assumptions about relative importance and uncovers little about the trade-offs between objectives. In contrast to scalarization, Pareto optimization does not require knowledge of relative importance and reveals the trade-offs between objectives. However, it introduces additional considerations in algorithm design. In this review, we describe pool-based and de novo generative approaches to multi-objective molecular discovery with a focus on Pareto optimization algorithms. We show how pool-based molecular discovery is a relatively direct extension of multi-objective Bayesian optimization and how the plethora of different generative models extend from single-objective to multi-objective optimization in similar ways using non-dominated sorting in the reward function (reinforcement learning) or to select molecules for retraining (distribution learning) or propagation (genetic algorithms). Finally, we discuss some remaining challenges and opportunities in the field, emphasizing the opportunity to adopt Bayesian optimization techniques into multi-objective de novo design

Balancing Exploration and Exploitation: Disentangled β\beta-CVAE in De Novo Drug Design

Deep generative models have recently emerged as a promising de novo drug design method. In this respect, deep generative conditional variational autoencoder (CVAE) models are a powerful approach for generating novel molecules with desired drug-like properties. However, molecular graph-based models with disentanglement and multivariate explicit latent conditioning have not been fully elucidated. To address this, we proposed a molecular-graph $\beta$-CVAE model for de novo drug design. Here, we empirically tuned the value of disentanglement and assessed its ability to generate molecules with optimised univariate- or-multivariate properties. In particular, we optimised the octanol-water partition coefficient (ClogP), molar refractivity (CMR), quantitative estimate of drug-likeness (QED), and synthetic accessibility score (SAS). Results suggest that a lower $\beta$ value increases the uniqueness of generated molecules (exploration). Univariate optimisation results showed our model generated molecular property averages of ClogP = 41.07% $\pm$ 0.01% and CMR 66.76% $\pm$ 0.01% by the Ghose filter. Multivariate property optimisation results showed that our model generated an average of 30.07% $\pm$ 0.01% molecules for both desired properties. Furthermore, our model improved the QED and SAS (exploitation) of molecules generated. Together, these results suggest that the $\beta$-CVAE could balance exploration and exploitation through disentanglement and is a promising model for de novo drug design, thus providing a basis for future studies