title: Rational design of angiotensin-I-converting enzyme inhibitory peptides by integrating in silico modeling and an in vitro assay.
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).
authors.affiliation: Department of Cardiology, Southwest Hospital, Third Military Medical, University and Chongqing Institute of Interventional Cardiology, Chongqing 400038, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jing
authors.forename: Jian
authors.initials: J
authors.lastname: Feng
authors.forename: De
authors.initials: D
authors.lastname: Li
authors.forename: Jianping
authors.initials: J
authors.lastname: Liu
authors.forename: Guoxiang
authors.initials: G
authors.lastname: He
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D008024:Ligands; D010455:Peptides; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A