Novel multitarget ACE inhibitory peptides from grass carp swim bladder: Identification and potential antihypertensive mechanism

Sustainable utilization of aquaculture byproducts is imperative for advancing circular bioeconomy in food systems. This study developed an integrated <i>in silico</i>-<i>in vitro</i> screening strategy to identify novel angiotensin-converting enzyme (ACE) inhibitory peptides from grass carp swim bladder hydrolysates. Two novel peptides, FPSPFR (749.86 Da) and LWDPPEGAP (981.06 Da), were screened with IC₅₀ values of 81.34 μM and 206.91 μM, respectively. Kinetic characterization revealed non-competitive inhibition alongside exceptional gastrointestinal stability. Molecular docking showed strong binding affinities (-10.0 and -9.8 kcal/mol) <i>via</i> hydrogen bonding and hydrophobic interactions, while molecular dynamics simulations confirmed stable binding conformations. Network pharmacology and docking analysis suggested FPSPFR's potential antihypertensive effects through interactions with core targets including ALB, AKT1, SRC, ACE, MMP9 and STAT3. These results validate <i>in silico</i> analysis combined with <i>in vitro</i> assessments as an effective strategy for ACE inhibitory peptides discovery. Swim bladder-derived peptides demonstrated potent antihypertensive effects while enabling sustainable valorization of underutilized fishery processing byproducts, offering a viable pathway for functional food development and pharmaceutical applications.