Integration of Multiple Analytical and Computational Tools for the Discovery of High‐Potency Enzyme Inhibitors from Herbal Medicines

Herbal medicines (HMs) are an important source of drugs. In this study, an efficient strategy integrating ultrafiltration LC–MS, microplate bioassays, and molecular docking was proposed to screen high-potency enzyme inhibitors from HMs. Using this strategy, the structure–activity relationships (SARs) including binding-affinity-based SAR, enzymatic-activity-based SAR, and structural-complementarity-based SAR of compounds in an HM can be analyzed to provide abundant information for drug discovery. A prominent advantage of the approach is that it offers a multidimensional perspective to understand enzyme–ligand interactions, which could help to avoid false-positive screening results brought by a single method. By using xanthine oxidase (XOD) as an illustrative case, two types of potent XOD inhibitors, including flavones and coumarins, were successfully screened out from an HM of Ginkgo biloba. The study is expected to set a solid foundation for multidisciplinary cooperation in drug discovery.