Abstract
Angiotensin-I Converting Enzyme (ACE) plays a pivotal role in regulating hypertension. Inhibition of ACE by potent inhibitors is an excellent approach to treating high blood pressure and related cardiac ailments. Dietary proteins are a good source of bioactive peptides with a broad spectrum of pharmacological activities. An attempt has been made in this investigation to study the structure–activity relationship of a novel octapeptide ACE inhibitor having the amino acid sequence: isoleucine-glycine-proline-glycine-proline-phenylalanine-serine-arginine (IGPGPFSR; molecular weight 830.953 Dalton), isolated and identified from Lamellidens marginalis, a freshwater edible Mollusca and still underexploited for its health benefit molecules. The low molecular weight ACE inhibitory peptide has been evaluated for enzyme kinetics, isothermal titration calorimetry (ITC), and site-specific docking simulation study. Lineweaver–Burk plot analysis and ITC reveal that peptide-IGPGPFSR is a non-competitive inhibitor. Molecular docking simulation further confirms that this antihypertensive peptide bound to ACE by hydrogen bond interaction between Asp410, Lys468, His470, Arg479, and Glu104 of the enzyme with Ile1, Pro3, Gly4, Ser7, and Arg8 of the peptide respectively. Interaction of Pro5 and Phe6 of the peptide displaces the zinc (Zn2+) ion from the active site which results in the incapability of the substrate: Hippuryl-L-Histidyl-L-Leucine (HHL) to bind to the active site of the enzyme and ultimately leads to inhibition of ACE. Present observations suggest that this novel antihypertensive octapeptide-IGPGPFSR is a potent inhibitor of ACE and can be used as an auxiliary for nutraceutical therapy against hypertension. Moreover, the underlying mechanism of ACE inhibition will help in widening our knowledge of drug design against enzyme targets.
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Acknowledgements
This study was financially supported by the University Grants Commission, New Delhi, India [File No-42-214/2013(SR)].
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Conceptualisation: TKD, PD, JC, Methodology: MD, AH, RC, TKD, Formal analysis and Investigation: MD, AH, RC, AG, TKD, SR, Writing- Original Draft preparation: MD, JC, Writing- Review and editing: MD, PD, JC, Resources: PD, JC, Supervision: PD, JC.
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Das, M., Halder, A., Chatterjee, R. et al. In Vitro Structure–Activity Relationship Study of a Novel Octapeptide Angiotensin-I Converting Enzyme (ACE) Inhibitor from the Freshwater Mussel Lamellidens marginalis. Int J Pept Res Ther 29, 18 (2023). https://doi.org/10.1007/s10989-023-10495-5
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DOI: https://doi.org/10.1007/s10989-023-10495-5