The target-based drug discovery (TBDD) alongside the resurgence of phenotypic drug discovery (PDD) constitute the dual-track paradigm for modern drug discovery. These two approaches are interactively applied and validated, accelerating the R&D of novel therapeutics. The microscopic structure of drugs (molecular structure and formulation properties) forms the basis for their macroscopic representations (pharmacological efficacy, physicochemical properties, adverse reactions, etc.), while these macroscopic properties represent the emergent characteristics arising from the interactions of microstructures. The applications of principles and techniques from molecular biology, biophysics, biochemistry, and analytical chemistry reveal the material essence and mechanisms of action at the micro-level, simultaneously mapping them onto various macro-level manifestations. Over three decades ago, the Chinese traditional medicines Danggui Lu Hui Wan (Angelica sinensis and Aloe Pill), investigated through phenotypic research, led to the development of meisoindigo for the treatment of chronic myeloid leukemia. Although its molecular target and mechanism of action were poorly understood at the time, it remains in clinical use today. Advances in science and technology have now enabled rigorous experimental design and execution, revealing meisoindigo's function as a molecular glue. It binds the target protein PKMYT1 while recruiting the E3 ligase TRIM25, forming a ternary complex that catalyzes the target protein's entry into the ubiquitin-proteasome system for degradation and functional loss. This micro-level elucidation explains its macro-level therapeutic efficacy. This article attempts to provide a concise commentary on this over-30-year R&D chain: "Danggui Lu Hui Wan → Indigo Naturalis → Indirubin → Meisoindigo → Molecular Glue, " aiming to bridge the gap between PDD and TBDD.

phenotypic research  /  mechanism of action  /  Danggui Lu Hui Wan  /  meisoindigo  /  molecular glue