A Unified View of Deep Learning for Reaction and Retrosynthesis Prediction: Current Status and Future Challenges

Reaction and retrosynthesis prediction are fundamental tasks in computational chemistry that have recently garnered attention from both the machine learning and drug discovery communities. Various deep learning approaches have been proposed to tackle these problems, and some have achieved initial success. In this survey, we conduct a comprehensive investigation of advanced deep learning-based models for reaction and retrosynthesis prediction. We summarize the design mechanisms, strengths, and weaknesses of state-of-the-art approaches. Then, we discuss the limitations of current solutions and open challenges in the problem itself. Finally, we present promising directions to facilitate future research. To our knowledge, this paper is the first comprehensive and systematic survey that seeks to provide a unified understanding of reaction and retrosynthesis prediction.

Doubly Stochastic Graph-based Non-autoregressive Reaction Prediction

Organic reaction prediction is a critical task in drug discovery. Recently, researchers have achieved non-autoregressive reaction prediction by modeling the redistribution of electrons, resulting in state-of-the-art top-1 accuracy, and enabling parallel sampling. However, the current non-autoregressive decoder does not satisfy two essential rules of electron redistribution modeling simultaneously: the electron-counting rule and the symmetry rule. This violation of the physical constraints of chemical reactions impairs model performance. In this work, we propose a new framework called that combines two doubly stochastic self-attention mappings to obtain electron redistribution predictions that follow both constraints. We further extend our solution to a general multi-head attention mechanism with augmented constraints. To achieve this, we apply Sinkhorn's algorithm to iteratively update self-attention mappings, which imposes doubly conservative constraints as additional informative priors on electron redistribution modeling. We theoretically demonstrate that our can simultaneously satisfy both rules, which the current decoder mechanism cannot do. Empirical results show that our approach consistently improves the predictive performance of non-autoregressive models and does not bring an unbearable additional computational cost.

Graph-adaptive Rectified Linear Unit for Graph Neural Networks

Graph Neural Networks (GNNs) have achieved remarkable success by extending traditional convolution to learning on non-Euclidean data. The key to the GNNs is adopting the neural message-passing paradigm with two stages: aggregation and update. The current design of GNNs considers the topology information in the aggregation stage. However, in the updating stage, all nodes share the same updating function. The identical updating function treats each node embedding as i.i.d. random variables and thus ignores the implicit relationships between neighborhoods, which limits the capacity of the GNNs. The updating function is usually implemented with a linear transformation followed by a non-linear activation function. To make the updating function topology-aware, we inject the topological information into the non-linear activation function and propose Graph-adaptive Rectified Linear Unit (GReLU), which is a new parametric activation function incorporating the neighborhood information in a novel and efficient way. The parameters of GReLU are obtained from a hyperfunction based on both node features and the corresponding adjacent matrix. To reduce the risk of overfitting and the computational cost, we decompose the hyperfunction as two independent components for nodes and features respectively. We conduct comprehensive experiments to show that our plug-and-play GReLU method is efficient and effective given different GNN backbones and various downstream tasks.

Modeling Scale-free Graphs for Knowledge-aware Recommendation

Aiming to alleviate data sparsity and cold-start problems of traditional recommender systems, incorporating knowledge graphs (KGs) to supplement auxiliary information has recently gained considerable attention. Via unifying the KG with user-item interactions into a tripartite graph, recent works explore the graph topologies to learn the low-dimensional representations of users and items with rich semantics. However, these real-world tripartite graphs are usually scale-free, the intrinsic hierarchical graph structures of which are underemphasized in existing works, consequently, leading to suboptimal recommendation performance. To address this issue and provide more accurate recommendation, we propose a knowledge-aware recommendation method with the hyperbolic geometry, namely Lorentzian Knowledge-enhanced Graph convolutional networks for Recommendation (LKGR). LKGR facilitates better modeling of scale-free tripartite graphs after the data unification. Specifically, we employ different information propagation strategies in the hyperbolic space to explicitly encode heterogeneous information from historical interactions and KGs. Our proposed knowledge-aware attention mechanism enables the model to automatically measure the information contribution, producing the coherent information aggregation in the hyperbolic space. Extensive experiments on three real-world benchmarks demonstrate that LKGR outperforms state-of-the-art methods by 2.2-29.9% of Recall@20 on Top-K recommendation.

FeatureNorm: L2 Feature Normalization for Dynamic Graph Embedding

Dynamic graphs arise in a plethora of practical scenarios such as social networks, communication networks, and financial transaction networks. Given a dynamic graph, it is fundamental and essential to learn a graph representation that is expected not only to preserve structural proximity but also jointly capture the time-evolving patterns. Recently, graph convolutional network (GCN) has been widely explored and used in non-Euclidean application domains. The main success of GCN, especially in handling dependencies and passing messages within nodes, lies in its approximation to Laplacian smoothing. As a matter of fact, this smoothing technique can not only encourage must-link node pairs to get closer but also push cannot-link pairs to shrink together, which potentially cause serious feature shrink or oversmoothing problem, especially when stacking graph convolution in multiple layers or steps. For learning time-evolving patterns, a natural solution is to preserve historical state and combine it with the current interactions to obtain the most recent representation. Then the serious feature shrink or oversmoothing problem could happen when stacking graph convolution explicitly or implicitly according to current prevalent methods, which would make nodes too similar to distinguish each other. To solve this problem in dynamic graph embedding, we analyze the shrinking properties in the node embedding space at first, and then design a simple yet versatile method, which exploits L2 feature normalization constraint to rescale all nodes to hypersphere of a unit ball so that nodes would not shrink together, and yet similar nodes can still get closer. Extensive experiments on four real-world dynamic graph datasets compared with competitive baseline models demonstrate the effectiveness of the proposed method.

MAGNN: Metapath Aggregated Graph Neural Network for Heterogeneous Graph Embedding

A large number of real-world graphs or networks are inherently heterogeneous, involving a diversity of node types and relation types. Heterogeneous graph embedding is to embed rich structural and semantic information of a heterogeneous graph into low-dimensional node representations. Existing models usually define multiple metapaths in a heterogeneous graph to capture the composite relations and guide neighbor selection. However, these models either omit node content features, discard intermediate nodes along the metapath, or only consider one metapath. To address these three limitations, we propose a new model named Metapath Aggregated Graph Neural Network (MAGNN) to boost the final performance. Specifically, MAGNN employs three major components, i.e., the node content transformation to encapsulate input node attributes, the intra-metapath aggregation to incorporate intermediate semantic nodes, and the inter-metapath aggregation to combine messages from multiple metapaths. Extensive experiments on three real-world heterogeneous graph datasets for node classification, node clustering, and link prediction show that MAGNN achieves more accurate prediction results than state-of-the-art baselines.