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Rational Design of Angiotensin‐I‐Converting Enzyme Inhibitory Peptides by Integrating in silico Modeling and an in vitro Assay
Author(s) -
Jing Tao,
Feng Jian,
Li De,
Liu Jianping,
He Guoxiang
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300132
Subject(s) - in silico , peptide , in vitro , inhibitory postsynaptic potential , chemistry , angiotensin converting enzyme , enzyme , rational design , amphiphile , mutant , combinatorial chemistry , active site , biochemistry , nanotechnology , biology , materials science , organic chemistry , neuroscience , gene , blood pressure , copolymer , endocrinology , polymer
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 (IC 50 decrease from 75.4 to 4.2 μ M ).