Molecular Characterization of Lasmiditan Binding to Human Serum Albumin: Site Preference, Structural Response, and Binding Energetics

Although lasmiditan (LASMI) is a recently introduced antimigraine drug with reported moderate plasma protein binding, the molecular determinants of its association with HSA remain poorly defined. Here, an integrated spectroscopic and computational approach was used to characterize HSA-LASMI complex formation, binding-site preference, and the accompanying structural response of the protein.

UV–Vis absorption, steady-state fluorescence quenching, FTIR, and circular dichroism spectroscopy were combined with site-marker displacement experiments, molecular docking, 100 ns molecular dynamics simulations, and MM/PBSA binding free-energy calculations. Competitive site-marker experiments indicated preferential LASMI binding within Sudlow site I in subdomain IIA. Complex formation was associated with quenching of intrinsic HSA fluorescence and modest protein structural reorganization.