文献类型：期刊文献

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

作者：Hu, Chao[3,4];Li, Song[1,2,3];Yang, Chenxing[3];Chen, Jun[3];Xiong, Yi[5,6];Fan, Guisheng[4];Liu, Hao[3];Hong, Liang[1,2,5,6]

机构：[1]Shanghai Jiao Tong Univ, Sch Phys & Astron, Shanghai 200240, Peoples R China;[2]Shanghai Jiao Tong Univ, Inst Nat Sci, Shanghai 200240, Peoples R China;[3]Shanghai Matwings Technol Co Ltd, Shanghai 200240, Peoples R China;[4]East China Univ Sci & Technol, Sch Informat Sci & Engn, Shanghai 200237, Peoples R China;[5]Shanghai Jiao Tong Univ, Sch Life Sci & Biotechnol, Shanghai 200240, Peoples R China;[6]Shanghai Jiao Tong Univ, Zhangjiang Inst Adv Study, Shanghai 201203, Peoples R China

年份：2023

卷号：15

期号：1

外文期刊名：JOURNAL OF CHEMINFORMATICS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001081692500001)】；

基金：This work was supported by the National Natural Science Foundation of China (11974239), the Innovation Program of Shanghai Municipal Education Commission (2019-01-07-00-02-E00076), the Student Innovation Center at Shanghai Jiao Tong University, and the Shanghai Artificial Intelligence Laboratory.

语种：英文

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

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.