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  • Title: Rational design of angiotensin-I-converting enzyme inhibitory peptides by integrating in silico modeling and an in vitro assay.
    Author: Jing T, Feng J, Li D, Liu J, He G.
    Journal: ChemMedChem; 2013 Jul; 8(7):1057-66. PubMed ID: 23740817.
    Abstract:
    Human angiotensin-I-converting enzyme (ACE) is a classic target of antihypertensive drugs and possesses a bulky, amphiphilic active pocket that is physicochemically compatible with a wide spectrum of small peptide ligands. Herein we describe a synthetic pipeline to directly optimize the atomic interactions between ACE in complex with its peptide ligands. By using this pipeline, we were able to derive thousands of peptides with potential ACE-inhibitory capacity, from which 15 structurally diverse, theoretically active samples were investigated systematically with respect to the structural, energetic, and dynamic aspects of their interactions with ACE. Subsequently, ACE-inhibitory activities of several highly promising candidates were evaluated in vitro using a standard spectrophotometric method. As might be expected, three of these candidates showed high inhibitory activities against ACE and others also significantly inhibited the enzymatic activity at low or moderate doses. Furthermore, one of these peptides, LHGPYP, was chosen for structural modification based on the details of its interaction with ACE using modeled structure data. Consequently, a Gly 3 Leu/Tyr 5 Ala double mutation on the peptide was assessed to obtain a more potent mutant LHLPAP, leading to a considerable increase in ACE-inhibitory activity (IC50 decrease from 75.4 to 4.2 μM).
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