Angiotensin-Converting Enzyme Inhibitory Peptide Derived from Ultrafine Lycium barbarum Pomace Powder: In Vitro and In Silico Analysis

This study aimed to identify the sequence and assess the stability of angiotensin-converting enzyme (ACE) inhibitory peptides derived from ultrafine Lycium barbarum pomace powder (u-LPP), while network pharmacology analysis was employed to explore potential mechanisms for heart failure with preserved ejection fraction (HFpEF) improvement. The peptides identified by LC–MS/MS were GPFN, LGGP, AGLP, and TAFP, among which GPFN had the highest activity (IC50 of 324.44 ± 8.93 μM). GPFN exhibits gastrointestinal enzyme hydrolysis resistance. Furthermore, after 2 h of incubation, GPFN could permeate Caco-2 cell monolayers through the paracellular route by passive diffusion. Molecular docking revealed that GPFN could stably bind to ACE (binding energy of −8.88 kcal/mol). Molecular dynamics (MD) simulation indicated that the ACE–GPFN complex had good stability. Network pharmacological analysis and molecular docking demonstrated strong interactions between GPFN and key targets, such as CASP3, MMP9, SRC, APP, ACE, and MMP2. GPFN might have the potential activity to improve HFpEF.