Novel Sleep-Promoting Peptides from Sea Cucumbers Targeting the GABAa Receptor Identified by a Multitechnique...

The study aimed to screen novel sleep-promoting oligopeptides from sea cucumbers. Proteolysis simulation, conducted on proteins that do not represent the primary structural components of the sea cucumber body wall, confirmed that alcalase and chymotrypsin were optimal for preparing sea cucumber oligopeptides. Two novel sleep-promoting peptides, Leu-Phe-Ala (LFA) and Thr-Phe-Trp (TFW), were successfully screened through bioinformatics tools, molecular docking, and pharmacophore models. Both LFA (520.5 ± 75.81 s) and TFW (188.3 ± 48.63 s) significantly shortened the sleep latency of PCPA-induced insomnia mice. Additionally, LFA alleviated anxiety-like behavior in insomnia mice. They ameliorated the imbalance of excitatory and inhibitory neurotransmitters in insomnia mice. LFA-GABAAR and TFW-GABAAR complexes interact via hydrogen bonds and hydrophobic forces, showing great structural stability. In conclusion, in silico and in vivo analysis can effectively and rapidly discover sleep-promoting peptides from sea cucumber proteins. This study provides a theoretical basis for identifying novel sleep-promoting constituents from natural proteins.