Drug Discovery from Complex Mixtures: Serendipity, Screening, and Characterization

Abstract

Natural products mixtures, as originally sourced in nature, are encountered in complex matrices that may contain useful active components at low concentrations, but also a number of unrelated molecular components, often in larger quantities. To detect and identify active principles can be challenging and depends on the process of sample preparation, along with the selection, design, and operation of the relevant assay. Sample preparation may entail extraction, chromatography, or some other concentration/purification step(s). The assays chosen may range from simple isolated enzyme assays, where the mixture is tested against a particular target, to phenotypic type assays where the growth, viability, or function of a cell or a tissue is being monitored. And in more sophisticated approaches, cellular systems may be so studied—even engineered for optimization—to incorporate a specific target-based screen in a cellular context. In many drug discovery settings, these assays have been miniaturized to enhance efficiency and throughput. Identification of “hits” (complex mixtures positive for the activity in question) can allow further purification of the mixture to “track” the active principle(s) and then to structurally identify them using chemical means. In some programs, the screening and chemistry work can be combined in integrated operations to maximize efficiency. Because of the complexity of cellular assay systems, and the vast complexity of natural products, many “serendipitous” discoveries have been encountered, identifying new chemical classes or new modes of biological action for known compounds.