2026-10-14T13:35:35Z https://api.figshare.com/v2/oai

oai:figshare.com:article/34029973 2026-09-30T05:17:13Z category_1 category_4 category_915 category_14 category_19 category_873 category_734 category_64 portal_63 item_type_6 month_year_09_2026

Molecular Characterization of Lasmiditan Binding to Human Serum Albumin: Site Preference, Structural Response, and Binding Energetics Tadeusz W. Inglot (25141774) Biophysics Biochemistry Physical Sciences not elsewhere classified Molecular Biology Pharmacology Chemical Sciences not elsewhere classified Biological Sciences not elsewhere classified Cancer marker displacement experiments human serum albumin circular dichroism spectroscopy 76 kj mol 73 ± 0 16 ± 0 g ., δ subtle lasmi concentration 96 μm lasmi molecular dynamics simulations state fluorescence quenching pbsa binding free major transport protein administered sudlow site accompanying structural response intrinsic hsa fluorescence understanding lasmiditan association lasmi complex formation structural response complex formation lasmi complex g </ lasmiditan binding although lasmiditan modeled complex molecular framework molecular docking molecular determinants molecular characterization − 21 therapeutic compounds supported stabilization substantially influence subdomain iia site preference sensitive signal potential relevance integrated spectroscopic helical content findings provide favorable binding energy calculations energetic stability dependent perturbation computational approach competitive site blood plasma binding compounds apparent decrease Human serum albumin (HSA), the major transport protein in blood plasma, can substantially influence the distribution of therapeutic compounds. 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. Far-UV CD measurements showed a subtle LASMI concentration-dependent perturbation of the HSA secondary-structure-sensitive signal, with an apparent decrease in α-helical content from 53.16 ± 0.05 to 50.73 ± 0.15% at 96 μM LASMI. Molecular dynamics simulations further supported stabilization of the HSA-LASMI complex, as reflected by lower backbone RMSD values and reduced residue flexibility relative to unbound HSA. Thermodynamic analysis indicated spontaneous and favorable binding (e.g., Δ<i>G</i>_298 K = −21.76 kJ mol^–1), while MM/PBSA calculations independently supported the energetic stability of the modeled complex. Together, these findings provide a molecular framework for understanding lasmiditan association with HSA and its potential relevance to plasma distribution and competition with co-administered Sudlow site I-binding compounds. 2026-09-30T00:00:00Z Text Journal contribution 10.1021/acsomega.6c08646.s001 https://figshare.com/articles/journal_contribution/Molecular_Characterization_of_Lasmiditan_Binding_to_Human_Serum_Albumin_Site_Preference_Structural_Response_and_Binding_Energetics/34029973 CC BY-NC 4.0