Machine intelligence decrypts β-lapachone as an allosteric 5-lipoxygenase inhibitor† †Electronic supplementary information (ESI) available: Supplementary figures, data and methods. See DOI: 10.1039/c8sc02634c

Using machine learning, targets were identified for β-lapachone. Using machine learning, targets were identified for β-lapachone. Resorting to biochemical assays, β-lapachone was validated as a potent, ligand efficient, allosteric and reversible modulator of 5-lipoxygenase (5-LO). Moreover, we provide a rationale for 5-LO modulation and show that inhibition of 5-LO is relevant for the anticancer activity of β-lapachone. This work demonstrates the power of machine intelligence to deconvolute complex phenotypes, as an alternative and/or complement to chemoproteomics and as a viable general approach for systems pharmacology studies.