Structure–Activity Relationship of Novel ACE Inhibitory Undecapeptides from Stropharia rugosoannulata by Molecular Interactions and Activity Analyses

Abstract

Undecapeptide is the central peptide molecule in the peptide base material of Stropharia rugosoannulata, and angiotensin-converting enzyme (ACE) plays a crucial role in hypertension. To fully explore the interaction mechanism and ACE-inhibitory activity of long-chain peptides from Stropharia rugosoannulata, the binding conformations of twenty-seven undecapeptides with the ACE receptor were revealed by molecule docking. The undecapeptide GQEDYDRLRPL with better receptor binding capacity and higher secondary mass spectral abundance was screened. All amino acid residues except proline in GQEDYDRLRPL interacted with the ACE receptor. GQEDYDRLRPL interfered with the receptor’s overall structure, with significant fluctuations in amino acid residues 340–355, including two residues in the receptor’s active pockets. The binding constants of GQEDYDRLRPL to the ACE receptors were at the μM level, with a kinetic binding constant of 9.26 × 10−7 M, which is a strong binding, and a thermodynamic binding constant of 3.06 × 10−6 M. Intermolecular interaction were exothermic, enthalpy-driven, and specific binding reactions. GQEDYDRLRPL had an IC50 value of 164.41 μmol/L in vitro and superior antihypertensive effects at low-gavage administration in vivo. Obtaining information on the interaction mechanism of ACE-inhibitory undecapeptides from S. rugosoannulata with the ACE receptor will help to develop and utilize ACE inhibitors of natural origin.

Revealing the ACE receptor binding properties and interaction mechanisms of salty oligopeptides from Stropharia rugosoannulata mushroom by molecular simulation and antihypertensive evaluation

“…Molecular dynamics simulations (MD) of the oligopeptides and the ACE receptor (PDB: 1O8A) were performed using the method described by Li et al 15 Amber99SB was chosen for the simulation force field, and the TIP3P model was used for water molecules. The receptor-oligopeptide complex was placed in the cubic box center of the simulation system, and the distance between the complex and the box was 1.0 nm.…”

“…The admetSAR website (https://lmmd.ecust.edu.cn/admetsar1/ predict/) was used to predict the toxicity, blood-brain barrier penetration, intestinal epithelial Caco-2 cell penetration, human intestinal absorption, and AMES oral toxicity of KSWDDFFTR. The in vivo hypotensive assay was performed using the method described by Li et al 15 Thirty-six elevenweek-old male SHR and Wistar rats weighing 200-250 g from SiPeiFu (Suzhou) Biotechnology Co., Ltd, Suzhou, China, were used. After a week of acclimatization feeding, the rats were randomly divided into six groups for a single gavage administration treatment.…”

“…At a mass concentration of 1 mg mL −1 , the peptide matrix had a salty evaluation value of 23.33 ± 0.11, an umami evaluation value of 13.17 ± 0.16, and a 50% ACE inhibitory concentration (IC 50 ) of 0.122 mg mL −1 , ABTS-free radical scavenging rate (%) was 72.24 ± 1.52, and a 50% DPP-IV inhibitory concentration of 6.62 mg mL −1 . [4][5][6] The ACE inhibitory activity of the S. rugosoannulata peptide matrix is more prominent than its antioxidant and DPP-IV inhibitory activity. Many ACE inhibitors have been identified from plant and animal protein hydrolysates and showed better ACE inhibitory effects in cellular models and blood pressure-lowering activity in animal models.…”