Microalgae-derived astaxanthin modulates the hormone receptor network associated with type 2 diabetes mellitus: An in-silico investigation supported by experimental literature.

Receptor-level mechanisms of microalgal astaxanthin (ASX) in T2DM remain largely unknown. In our study, the receptor-level binding compatibility and multi-target interaction profile of ASX with insulin, glucocorticoid, and glucagon-like peptide-1 (GLP-1) receptor models were investigated using a systematic and integrated in-silico workflow encompassing molecular docking, 1000 ns molecular dynamics (MD) simulations, molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) binding free energy calculations, density functional theory (DFT)-based HOMO-LUMO and molecular electrostatic potential (MEP) analyses, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses. Strong receptor-specific binding profiles were revealed for the target receptors associated with T2DM, with ASX binding energies ranging from -8.2 to -10.5 kcal/mol. Additionally, the presence of polar anchoring sites and hydrophobic contacts in these profiles supports the docking findings. MD simulation outputs also revealed that the ASX complexes were highly stable, while the MM/PBSA-based binding free energies of -45.86, -45.08, and -34.12 kcal/mol for glucagon-like peptide-1 receptor (GLP-1R), the glucocorticoid receptor, and insulin receptor (INSR), respectively, quantitatively supported this stability. Our DFT analysis findings also revealed ASX's low HOMO-LUMO energy gap, delocalized frontier molecular orbital distributions, and adaptive electrostatic properties, demonstrating the electronic compatibility of this microalgal ligand in the target receptor microenvironments. The ADMET findings of ASX revealed that, despite its limited intestinal permeability, it possesses favorable pharmacokinetic properties in terms of cardiac safety and CYP inhibition. In this context, microalgal ASX may represent a receptor-compatible multi-target candidate within the insulin-glucagon-GLP-1 axis, based on its conformational stabilization, thermodynamic compatibility, and electronic adaptation profiles.