WSDTNBI: a novel network-based inference method for virtual screening. Issue 4 (11th January 2022)

• Record Type: Journal Article
• Authors: Wu, Zengrui; Ma, Hui; Liu, Zehui; Zheng, Lulu; Yu, Zhuohang; Cao, Shuying; Fang, Wenqing; Wu, Lili; Li, Weihua; Liu, Guixia; Huang, Jin; Tang, Yun
• Is Part Of: Chemical science. Volume 13:Issue 4(2022)
• Page Start: 1060
• Page End: 1079
• Publication Date: 2022-01-11
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d1sc05613a
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : We developed a novel network-based method named wSDTNBI for the prediction of drug–target interactions, and applied it in the discovery of inverse agonists for retinoid-related orphan receptor γt. Abstract : In recent years, the rapid development of network-based methods for the prediction of drug–target interactions (DTIs) provides an opportunity for the emergence of a new type of virtual screening (VS), namely, network-based VS. Herein, we reported a novel network-based inference method named wSDTNBI. Compared with previous network-based methods that use unweighted DTI networks, wSDTNBI uses weighted DTI networks whose edge weights are correlated with binding affinities. A two-pronged approach based on weighted DTI and drug–substructure association networks was employed to calculate prediction scores. To show the practical value of wSDTNBI, we performed network-based VS on retinoid-related orphan receptor γt (RORγt), and purchased 72 compounds for experimental validation. Seven of the purchased compounds were confirmed to be novel RORγt inverse agonists by in vitro experiments, including ursonic acid and oleanonic acid with IC50 values of 10 nM and 0.28 μM, respectively. Moreover, the direct contact between ursonic acid and RORγt was confirmed using the X-ray crystal structure, and in vivo experiments demonstrated that ursonic acid and oleanonic acid have therapeutic effects on multiple sclerosis. These results indicate that wSDTNBI might be a powerful tool for network-based VS in drug discovery.