Describe Molecules by a Heterogeneous Graph Neural Network with Transformer-like Attention for Supervised Property Predictions.

Machine learning and deep learning have facilitated various successful studies of molecular property predictions. The rapid development of natural language processing and graph neural network (GNN) further pushed the state-of-the-art prediction performance of molecular property to a new level. A geometric graph could describe a molecular structure with atoms as the nodes and bonds as the edges. Therefore, a graph neural network may be trained to better represent a molecular structure. The existing GNNs assumed homogeneous types of atoms and bonds, which may miss important information between different types of atoms or bonds. This study represented a molecule using a heterogeneous graph neural network (MolHGT), in which there were different types of nodes and different types of edges. A transformer reading function of virtual nodes was proposed to aggregate all the nodes, and a molecule graph may be represented from the hidden states of the virtual nodes. This proof-of-principle study demonstrated that the proposed MolHGT network improved the existing studies of molecular property predictions. The source code and the training/validation/test splitting details are available at https://github.com/zhangruochi/Mol-HGT.

Deep scaffold hopping with multimodal transformer neural networks.

Scaffold hopping is a central task of modern medicinal chemistry for rational drug design, which aims to design molecules of novel scaffolds sharing similar target biological activities toward known hit molecules. Traditionally, scaffolding hopping depends on searching databases of available compounds that can't exploit vast chemical space. In this study, we have re-formulated this task as a supervised molecule-to-molecule translation to generate hopped molecules novel in 2D structure but similar in 3D structure, as inspired by the fact that candidate compounds bind with their targets through 3D conformations. To efficiently train the model, we curated over 50 thousand pairs of molecules with increased bioactivity, similar 3D structure, but different 2D structure from public bioactivity database, which spanned 40 kinases commonly investigated by medicinal chemists. Moreover, we have designed a multimodal molecular transformer architecture by integrating molecular 3D conformer through a spatial graph neural network and protein sequence information through Transformer. The trained DeepHop model was shown able to generate around 70% molecules having improved bioactivity together with high 3D similarity but low 2D scaffold similarity to the template molecules. This ratio was 1.9 times higher than other state-of-the-art deep learning methods and rule- and virtual screening-based methods. Furthermore, we demonstrated that the model could generalize to new target proteins through fine-tuning with a small set of active compounds. Case studies have also shown the advantages and usefulness of DeepHop in practical scaffold hopping scenarios.

XGraphBoost: Extracting Graph Neural Network-Based Features for a Better Prediction of Molecular Properties.

Determining the properties of chemical molecules is essential for screening candidates similar to a specific drug. These candidate molecules are further evaluated for their target binding affinities, side effects, target missing probabilities, etc. Conventional machine learning algorithms demonstrated satisfying prediction accuracies of molecular properties. A molecule cannot be directly loaded into a machine learning model, and a set of engineered features needs to be designed and calculated from a molecule. Such hand-crafted features rely heavily on the experiences of the investigating researchers. The concept of graph neural networks (GNNs) was recently introduced to describe the chemical molecules. The features may be automatically and objectively extracted from the molecules through various types of GNNs, e.g., GCN (graph convolution network), GGNN (gated graph neural network), DMPNN (directed message passing neural network), etc. However, the training of a stable GNN model requires a huge number of training samples and a large amount of computing power, compared with the conventional machine learning strategies. This study proposed the integrated framework XGraphBoost to extract the features using a GNN and build an accurate prediction model of molecular properties using the classifier XGBoost. The proposed framework XGraphBoost fully inherits the merits of the GNN-based automatic molecular feature extraction and XGBoost-based accurate prediction performance. Both classification and regression problems were evaluated using the framework XGraphBoost. The experimental results strongly suggest that XGraphBoost may facilitate the efficient and accurate predictions of various molecular properties. The source code is freely available to academic users at https://github.com/chenxiaowei-vincent/XGraphBoost.git.