Fragment-based deep molecular generation using hierarchical chemical graph representation and multi-resolution graph variational autoencoder. 2023

Zhenxiang Gao, and Xinyu Wang, and Blake Blumenfeld Gaines, and Xuetao Shi, and Jinbo Bi, and Minghu Song
Department of Computer Science and Engineering, University of Connecticut, Storrs, 06269, CT.

Graph generative models have recently emerged as an interesting approach to construct molecular structures atom-by-atom or fragment-by-fragment. In this study, we adopt the fragment-based strategy and decompose each input molecule into a set of small chemical fragments. In drug discovery, a few drug molecules are designed by replacing certain chemical substituents with their bioisosteres or alternative chemical moieties. This inspires us to group decomposed fragments into different fragment clusters according to their local structural environment around bond-breaking positions. In this way, an input structure can be transformed into an equivalent three-layer graph, in which individual atoms, decomposed fragments, or obtained fragment clusters act as graph nodes at each corresponding layer. We further implement a prototype model, named multi-resolution graph variational autoencoder (MRGVAE), to learn embeddings of constituted nodes at each layer in a fine-to-coarse order. Our decoder adopts a similar but conversely hierarchical structure. It first predicts the next possible fragment cluster, then samples an exact fragment structure out of the determined fragment cluster, and sequentially attaches it to the preceding chemical moiety. Our proposed approach demonstrates comparatively good performance in molecular evaluation metrics compared with several other graph-based molecular generative models. The introduction of the additional fragment cluster graph layer will hopefully increase the odds of assembling new chemical moieties absent in the original training set and enhance their structural diversity. We hope that our prototyping work will inspire more creative research to explore the possibility of incorporating different kinds of chemical domain knowledge into a similar multi-resolution neural network architecture.

UI MeSH Term Description Entries
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D016571 Neural Networks, Computer A computer architecture, implementable in either hardware or software, modeled after biological neural networks. Like the biological system in which the processing capability is a result of the interconnection strengths between arrays of nonlinear processing nodes, computerized neural networks, often called perceptrons or multilayer connectionist models, consist of neuron-like units. A homogeneous group of units makes up a layer. These networks are good at pattern recognition. They are adaptive, performing tasks by example, and thus are better for decision-making than are linear learning machines or cluster analysis. They do not require explicit programming. Computational Neural Networks,Connectionist Models,Models, Neural Network,Neural Network Models,Neural Networks (Computer),Perceptrons,Computational Neural Network,Computer Neural Network,Computer Neural Networks,Connectionist Model,Model, Connectionist,Model, Neural Network,Models, Connectionist,Network Model, Neural,Network Models, Neural,Network, Computational Neural,Network, Computer Neural,Network, Neural (Computer),Networks, Computational Neural,Networks, Computer Neural,Networks, Neural (Computer),Neural Network (Computer),Neural Network Model,Neural Network, Computational,Neural Network, Computer,Neural Networks, Computational,Perceptron
D055808 Drug Discovery The process of finding chemicals for potential therapeutic use. Drug Prospecting,Discovery, Drug,Prospecting, Drug
D019985 Benchmarking Method of measuring performance against established standards of best practice. Benchmarking, Health Care,Benchmarks,Best Practice Analysis,Metrics,Benchmark,Benchmarking, Healthcare,Analysis, Best Practice,Health Care Benchmarking,Healthcare Benchmarking

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