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Open AccessReview

Considerations for Docking of Selective Angiotensin-Converting Enzyme Inhibitors

Centro de Bioinformática y Simulación Molecular (CBSM), Universidad de Talca, 1 Poniente No. 1141, Casilla 721, Talca 3460000, Chile
Academic Editor: Marilisa Leone
Molecules 2020, 25(2), 295; https://doi.org/10.3390/molecules25020295
Received: 21 December 2019 / Revised: 7 January 2020 / Accepted: 8 January 2020 / Published: 11 January 2020
(This article belongs to the Special Issue Computational Methods for Drug Discovery and Design)
The angiotensin-converting enzyme (ACE) is a two-domain dipeptidylcarboxypeptidase, which has a direct involvement in the control of blood pressure by performing the hydrolysis of angiotensin I to produce angiotensin II. At the same time, ACE hydrolyzes other substrates such as the vasodilator peptide bradykinin and the anti-inflammatory peptide N-acetyl-SDKP. In this sense, ACE inhibitors are bioactive substances with potential use as medicinal products for treatment or prevention of hypertension, heart failures, myocardial infarction, and other important diseases. This review examined the most recent literature reporting ACE inhibitors with the help of molecular modeling. The examples exposed here demonstrate that molecular modeling methods, including docking, molecular dynamics (MD) simulations, quantitative structure-activity relationship (QSAR), etc, are essential for a complete structural picture of the mode of action of ACE inhibitors, where molecular docking has a key role. Examples show that too many works identified ACE inhibitory activities of natural peptides and peptides obtained from hydrolysates. In addition, other works report non-peptide compounds extracted from natural sources and synthetic compounds. In all these cases, molecular docking was used to provide explanation of the chemical interactions between inhibitors and the ACE binding sites. For docking applications, most of the examples exposed here do not consider that: (i) ACE has two domains (nACE and cACE) with available X-ray structures, which are relevant for the design of selective inhibitors, and (ii) nACE and cACE binding sites have large dimensions, which leads to non-reliable solutions during docking calculations. In support of the solution of these problems, the structural information found in Protein Data Bank (PDB) was used to perform an interaction fingerprints (IFPs) analysis applied on both nACE and cACE domains. This analysis provides plots that identify the chemical interactions between ligands and both ACE binding sites, which can be used to guide docking experiments in the search of selective natural components or novel drugs. In addition, the use of hydrogen bond constraints in the S2 and S2′ subsites of nACE and cACE are suggested to guarantee that docking solutions are reliable. View Full-Text
Keywords: angiotensin-converting enzyme inhibitors; docking; interaction fingerprints; drug selectivity; rational drug design angiotensin-converting enzyme inhibitors; docking; interaction fingerprints; drug selectivity; rational drug design
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MDPI and ACS Style

Caballero, J. Considerations for Docking of Selective Angiotensin-Converting Enzyme Inhibitors. Molecules 2020, 25, 295.

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