Predicting drug synergy using a network propagation inspired machine learning framework

可解释性 药品 相互作用体 机器学习 机制(生物学) 药物重新定位 人工智能 计算生物学 生物网络 计算机科学 可扩展性 生物 生物信息学 药理学 基因 生物化学 哲学 认识论 数据库
作者
Qing Jin,Xianze Zhang,D Huo,Hongbo Xie,Denan Zhang,Lei Liu,Yashuang Zhao,Xiujie Chen
出处
期刊:Briefings in Functional Genomics [Oxford University Press]
标识
DOI:10.1093/bfgp/elad056
摘要

Combination therapy is a promising strategy for cancers, increasing therapeutic options and reducing drug resistance. Yet, systematic identification of efficacious drug combinations is limited by the combinatorial explosion caused by a large number of possible drug pairs and diseases. At present, machine learning techniques have been widely applied to predict drug combinations, but most studies rely on the response of drug combinations to specific cell lines and are not entirely satisfactory in terms of mechanism interpretability and model scalability. Here, we proposed a novel network propagation-based machine learning framework to predict synergistic drug combinations. Based on the topological information of a comprehensive drug-drug association network, we innovatively introduced an affinity score between drug pairs as one of the features to train machine learning models. We applied network-based strategy to evaluate their therapeutic potential to different cancer types. Finally, we identified 17 specific-, 21 general- and 40 broad-spectrum antitumor drug combinations, in which 69% drug combinations were validated by vitro cellular experiments, 83% drug combinations were validated by literature reports and 100% drug combinations were validated by biological function analyses. By quantifying the network relationships between drug targets and cancer-related driver genes in the human protein-protein interactome, we show the existence of four distinct patterns of drug-drug-disease relationships. We also revealed that 32 biological pathways were correlated with the synergistic mechanism of broad-spectrum antitumor drug combinations. Overall, our model offers a powerful scalable screening framework for cancer treatments.
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