Evaluation of Artificial Intelligence in Participating Structure-Based Virtual Screening for Identifying Novel...

Interleukin-1 receptor associated kinase-1 (IRAK1) exhibits important roles in inflammation, infection, and autoimmune diseases; however, only a few inhibitors have been discovered. In this study, at first, a discriminatory structure-based virtual screening (SBVS) was employed, but only one active compound (compound 1, IC₅₀ = 2.25 μM) was identified. The low hit rate (2.63%) which derives from the weak discriminatory power of docking among high-scored molecules was observed in our virtual screening (VS) process for IRAK1 inhibitor. Furthermore, an artificial intelligence (AI) method, which employed a support vector machine (SVM) model, integrated information of molecular docking, pharmacophore scoring and molecular descriptors was constructed to enhance the traditional IRAK1-VS protocol. Using AI, it was found that VS of IRAK1 inhibitors excluded by over 50% of the inactive compounds, which could significantly improve the prediction accuracy of the SBVS model. Moreover, four active molecules (two of which exhibited comparative IC₅₀ with compound 1) were accurately identified from a set of highly similar candidates. Amongst, compounds with better activity exhibited good selectivity against IRAK4. The AI assisted workflow could serve as an effective tool for enhancement of SBVS.