Pharmacophore-based structure optimization of angiotensin converting enzyme inhibitory peptide

Abstract

Chemical feature based pharmacophore models were generated for an angiotensin converting enzyme (ACE) inhibitory peptide using the Discovery Studio 2.0 pharmacophore modeling approach. The pharmacophore hypothesis selected has five features (one negative ionizable region, one hydrogen bond donor, one hydrogen bond acceptor and two hydrophobic functional groups). Additionally, ACE inhibitory hexapeptide previously obtained from silkworm pupae protein was optimized to target the ACE based on the selected pharmacophore. The results suggest that tri-peptide (thr-val-phe) may be structural determinant of ACE activity. Docking studies further provided confidence for the validity of the selected pharmacophore model to perform structure optimization of the ACE inhibitory peptide.angiotensin converting enzyme, inhibitory peptide, pharmacophore model, docking

Angiotensin Converting Enzyme (ACE) Inhibitory Peptides: Production and Implementation of Functional Food

“…This model also confirms binding site amino acidic residues, which play an essential role in ACE-peptide interactions: Thr282, Ala354, Val379, His383, Glu384, Phe391, Phe457, Lys511 and Phe512 [101,102]. In particular, interaction of the hydrogen-bond acceptor feature of the peptide TVF with His383 has been predicted, with the peptide binding in the predicted orientation and the interaction pattern satisfying the expected hydrophobic features [101].…”

“…In a recent work, Wang et al [101] present a new pharmacophore model that can help researchers in identifying functional groups and chemical features in the active compounds, thus improving the chance of finding or synthesizing new potent compounds that can become successful products. The authors generated ten pharmacophore models for the ACE inhibitory peptides with the same chemical features: one negative ionizable region, one hydrogen bond donor, one hydrogen bond acceptor and two hydrophobic functional groups.…”

“…For example, only the second moiety of the exapeptide SEPTVF from silk worm pupae protein (actual IC 50 : 324 μmol·L 1 ) is shown to play a role in binding ACE. TVF moiety maps in a way similar to LKP: two hydrophobic functional groups map respectively to valine and phenylalanine side chains; the negative ionizable functional group maps to the phenylalanine carboxyl group; the hydrogen bond donor and acceptor map respectively to threonine and valine amide carbonyl groups [101].…”

Tryptophan-containing milk protein-derived dipeptides inhibit xanthine oxidase

“…Trp has been described for its central role as a precursor of biomolecules such as melatonin, serotonin and dynorphin [22,39] and for its antioxidant properties [48,60]. Similarly, Val-Trp has been associated with various bioactive properties including angiotensin-converting enzyme (ACE) inhibition [6,37,64,67,74,89,91,93,94] and for -glucosidase inhibition [58,66]. The reverse peptide Trp-Val has also been described as an ACE inhibitor [67] and an anti-oxidant [31].…”