Tag and Snag: A New Platform for Bioactive Natural Product Screening from Mixtures.

Natural products provide an unparalleled diversity of small molecules to fuel drug screening efforts, but deconvoluting the pharmacological activity of natural product mixtures to identify key bioactive compounds remains a vexing and labor-intensive process. Therefore, we have developed a new platform to probe the non-specific pharmacological potential of compounds present in common dietary supplements via shotgun derivatization with isotopically labeled propanoic acid, a live cell affinity assay, which was used to selectively recognize the population of compounds which bind tightly to HeLa cells in culture, and a computational LC-MS data analysis of isotopically labeled compounds from cell lysate. The data analysis showed that hundreds of compounds were successfully derivatized in each extract, and dozens of those compounds showed high affinity for HeLa cells. In total, over a thousand isotopically labeled compounds were screened for cell affinity across three separate experiments, resulting in the identification of several known bioactive compounds with specific protein targets and six previously unreported structures. The new natural products include three tulsinol compounds which were isolated from