Although natural products have traditionally played an important role in therapeutic discovery and development, rediscovery of known compound classes is increasingly hampering novel compound development. 1 To address this issue, our laboratory is developing new methods for the direct mechanistic and chemical characterization of small molecules in complex mixtures. 2 Using a combination of multi-parametric high-throughput screening assays that report on compound modes of action, and untargeted metabolomics methods that describe the chemical complexity of natural products samples, we are creating pipelines for novel bioactive compound discovery. 3 These methods employ statistical methods to relate the presence or absence of compounds and compound classes to the presence or absence of specific phenotypes on screening libraries, providing a mechanism for the direct chemical and phenotypic profiling for all bioactive constituents from any natural products mixture. Recent results from this new platform will be presented.
(1) Pye, C. R.; Bertin, M. J.; Lokey, R. S.; Gerwick, W. H.; Linington, R. G. Proc. Natl. Acad. Sci. U.S.A. 2017, 114 (22), 5601.
(2) Ochoa, J. L.; Sanchez, L. M.; Koo, B.-M.; Doherty, J. S.; Rajendram, M.; Huang, K. C.; Gross, C. A.; Linington, R. G. ACS Infect. Dis. 2018, 4 (1), 59.
(3) Kurita, K. L.; Glassey, E.; Linington, R. G. P. Natl. Acad. Sci. U.S.A. 2015, 112 (39), 11999.