ScaffoldGVAE: scaffold generation and hopping of drug molecules via a variational autoencoder based on multi-view graph neural networks

Journal of Cheminformatics

Methodology

Guisheng Fan¹  Yi Xiong²  Liang Hong³  Song Li⁴  Jun Chen⁵  Chenxing Yang⁵  Hao Liu⁵  Chao Hu⁶ 

[1] School of Information Science and Engineering, East China University of Science and Technology, 200237, Shanghai, China;School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200240, Shanghai, China;Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, 201203, Shanghai, China;School of Physics and Astronomy and Institute of Natural Sciences, Shanghai Jiao Tong University, 200240, Shanghai, China;School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200240, Shanghai, China;Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, 201203, Shanghai, China;School of Physics and Astronomy and Institute of Natural Sciences, Shanghai Jiao Tong University, 200240, Shanghai, China;Shanghai Matwings Technology Co., Ltd., 200240, Shanghai, China;Shanghai Matwings Technology Co., Ltd., 200240, Shanghai, China;Shanghai Matwings Technology Co., Ltd., 200240, Shanghai, China;School of Information Science and Engineering, East China University of Science and Technology, 200237, Shanghai, China;

关键词: Drug design;    Molecule generation;    Scaffold hopping;    Variational autoencoder;    Multi-view graph neural networks;   

DOI  :  10.1186/s13321-023-00766-0

 received in 2023-08-11, accepted in 2023-09-25,  发布年份 2023

来源: Springer

【 摘 要 】

In recent years, drug design has been revolutionized by the application of deep learning techniques, and molecule generation is a crucial aspect of this transformation. However, most of the current deep learning approaches do not explicitly consider and apply scaffold hopping strategy when performing molecular generation. In this work, we propose ScaffoldGVAE, a variational autoencoder based on multi-view graph neural networks, for scaffold generation and scaffold hopping of drug molecules. The model integrates several important components, such as node-central and edge-central message passing, side-chain embedding, and Gaussian mixture distribution of scaffolds. To assess the efficacy of our model, we conduct a comprehensive evaluation and comparison with baseline models based on seven general generative model evaluation metrics and four scaffold hopping generative model evaluation metrics. The results demonstrate that ScaffoldGVAE can explore the unseen chemical space and generate novel molecules distinct from known compounds. Especially, the scaffold hopped molecules generated by our model are validated by the evaluation of GraphDTA, LeDock, and MM/GBSA. The case study of generating inhibitors of LRRK2 for the treatment of PD further demonstrates the effectiveness of ScaffoldGVAE in generating novel compounds through scaffold hopping. This novel approach can also be applied to other protein targets of various diseases, thereby contributing to the future development of new drugs. Source codes and data are available at https://github.com/ecust-hc/ScaffoldGVAE.

【 授权许可】

CC BY   
© Springer Nature Switzerland AG 2023

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