WSDTNBI: a novel network-based inference method for virtual screening.

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.