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.
Rodrigues, T., Werner, M., Roth, J., Da Cruz, E. H. G., Marques, M. C., Akkapeddi, P., … Bernardes, G. J. L. (2018). Machine intelligence decrypts β-lapachone as an allosteric 5-lipoxygenase inhibitor. Chemical Science, 9(34), 6899–6903. https://doi.org/10.1039/c8sc02634c