Molecular Characterization of Lasmiditan Binding to Human Serum Albumin: Site Preference, Structural Response, and Binding Energetics
- 1Medical University of Lublin , , Jaczewskiego 4 , ,
Abstract
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., ΔG298 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.
Related
- Mechanical Rupture of DNA Tension-Gate Elements: Thresholds, Kinetics, and Energetics from Steered Molecular Dynamics
- Structural Characterization of New 8,17-Epoxybriarane Diterpenoids from the Octocoral Briareum stechei
- Structural insights into an aptainhibitor of the SARS-CoV-2 E protein using molecular docking, molecular dynamics, and biophysical analyses
- Molecular and functional characterization of a highly mosquitocidal Bacillus thuringiensis strain VCRC-B669
- STRUCTURAL AND MOLECULAR DYNAMICS ANALYSIS OF HUMAN β-DEFENSIN 1 VARIANTS REVEALS DISTINCT PERTURBATION SIGNATURES
BibTeX
@article{inglot2026molecular,
title = {{Molecular Characterization of Lasmiditan Binding to Human Serum Albumin: Site Preference, Structural Response, and Binding Energetics}},
author = {Tadeusz W. Inglot},
journal = {ACS Omega},
year = {2026},
month = sep,
doi = {10.1021/acsomega.6c08646},
url = {https://pubs.acs.org/acsodf/article/11/40/62126/5442113/Molecular-Characterization-of-Lasmiditan-Binding},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Molecular Characterization of Lasmiditan Binding to Human Serum Albumin: Site Preference, Structural Response, and Binding Energetics
AU - Tadeusz W. Inglot
PY - 2026
DA - 2026/09/30
JO - ACS Omega
DO - 10.1021/acsomega.6c08646
UR - https://pubs.acs.org/acsodf/article/11/40/62126/5442113/Molecular-Characterization-of-Lasmiditan-Binding
AB - 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., ΔG298 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.
SN - 2470-1343
ER -