Structural and molecular basis of angiotensin-converting enzyme by computational modeling: Insights into the mechanisms of different inhibitors

Li, Fang; Geng, Mingxian; Wang, Ji; Min, Weihong; Liu, Jingsheng

doi:10.1371/journal.pone.0215609

Cited by 38 publications

(30 citation statements)

References 34 publications

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“…The same authors (Qi et al [59]) investigated the interactions between the bioactive peptide GEF and both ACE domains by using docking and MD simulations. In other work, Fang et al [60] studied the interactions between three bioactive peptides (LIVT, YLVPH, and YLVR) and ACE by using docking and MD simulations. Authors results provide a theoretical basis for the design of ACE inhibitors as well as insight into the structural and molecular properties of ACE and the mechanisms of inhibition of the different peptide inhibitors [60].…”

Section: Molecular Modeling Applied To the Study Of Ace Inhibitors Inmentioning

confidence: 99%

“…In other work, Fang et al [60] studied the interactions between three bioactive peptides (LIVT, YLVPH, and YLVR) and ACE by using docking and MD simulations. Authors results provide a theoretical basis for the design of ACE inhibitors as well as insight into the structural and molecular properties of ACE and the mechanisms of inhibition of the different peptide inhibitors [60]. In other work, Tong et al [61] calculated amino acid descriptors and performed QSAR models applyed to 55 ACE tri-peptides inhibitors.…”

Section: Molecular Modeling Applied To the Study Of Ace Inhibitors Inmentioning

confidence: 99%

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Considerations for Docking of Selective Angiotensin-Converting Enzyme Inhibitors

Caballero

2020

Molecules

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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.

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Section: Molecular Modeling Applied To the Study Of Ace Inhibitors Inmentioning

confidence: 99%

Section: Molecular Modeling Applied To the Study Of Ace Inhibitors Inmentioning

confidence: 99%

Considerations for Docking of Selective Angiotensin-Converting Enzyme Inhibitors

Caballero

2020

Molecules

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“…However, it has been reported for them to have diverse side effects including hyperkalemia and skin rashes [11], impairment of renal function [12], and development of angioedema [13]. Therefore, peptides from natural sources were considered as alternative ACE inhibitors and attracted researchers' interest [14][15][16][17][18]. The structures of ACE complexes with various ligands including synthetic inhibitors and peptides are available in the Protein Data Bank (PDB).…”

Section: Introductionmentioning

confidence: 99%

“…Molecular dynamics (MD) simulations are known as a powerful tool for molecular modeling and investigating dynamics of proteins and have been applied to various systems successfully [25]. Recently, MD simulations of ACE with various ligands were reported for drug discovery and molecular modeling for interactions between the enzyme and potential inhibitors [14][15][16]18,26].…”

Section: Introductionmentioning

confidence: 99%

Spontaneous Hinge-Bending Motions of Angiotensin I Converting Enzyme: Role in Activation and Inhibition

Heo

Jung

et al. 2020

Molecules

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The inhibition of human angiotensin I converting enzyme (ACE) has been regarded as a promising approach for the treatment of hypertension. Despite research attempts over many years, our understanding the mechanisms of activation and inhibition of ACE is still far from complete. Here, we present results of all atom molecular dynamics simulations of ACE with and without ligands. Two types of inhibitors, competitive and mixed non-competitive, were used to model the ligand bound forms. In the absence of a ligand the simulation showed spontaneous large hinge-bending motions of multiple conversions between the closed and open states of ACE, while the ligand bound forms were stable in the closed state. Our simulation results imply that the equilibrium between pre-existing backbone conformations shifts in the presence of a ligand. The hinge-bending motion of ACE is considered as an essential to the enzyme function. A mechanistic model of activation and the inhibition may provide valuable information for novel inhibitors of ACE.

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“…Biopeptides with anti-ACE activities present in food can bind to the ACE and hinder its activity by altering blood pressure. Fang et al [84] showed different mechanisms of inhibition of anti-hypertensive biopeptides using a computational model.…”

Section: Cardiovascular Active Peptides Endowed With Ace-mediated Antmentioning

confidence: 99%

Cardiovascular Active Peptides of Marine Origin with ACE Inhibitory Activities: Potential Role as Anti-Hypertensive Drugs and in Prevention of SARS-CoV-2 Infection

Festa

Sansone

Brunet

et al. 2020

IJMS

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Growing interest in hypertension—one of the main factors characterizing the cardiometabolic syndrome (CMS)—and anti-hypertensive drugs raised from the emergence of a new coronavirus, SARS-CoV-2, responsible for the COVID19 pandemic. The virus SARS-CoV-2 employs the Angiotensin-converting enzyme 2 (ACE2), a component of the RAAS (Renin-Angiotensin-Aldosterone System) system, as a receptor for entry into the cells. Several classes of synthetic drugs are available for hypertension, rarely associated with severe or mild adverse effects. New natural compounds, such as peptides, might be useful to treat some hypertensive patients. The main feature of ACE inhibitory peptides is the location of the hydrophobic residue, usually Proline, at the C-terminus. Some already known bioactive peptides derived from marine resources have potential ACE inhibitory activity and can be considered therapeutic agents to treat hypertension. Peptides isolated from marine vertebrates, invertebrates, seaweeds, or sea microorganisms displayed important biological activities to treat hypertensive patients. Here, we reviewed the anti-hypertensive activities of bioactive molecules isolated/extracted from marine organisms and discussed the associated molecular mechanisms involved. We also examined ACE2 modulation in sight of SARS2-Cov infection prevention.

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Structural and molecular basis of angiotensin-converting enzyme by computational modeling: Insights into the mechanisms of different inhibitors

Cited by 38 publications

References 34 publications

Considerations for Docking of Selective Angiotensin-Converting Enzyme Inhibitors

Considerations for Docking of Selective Angiotensin-Converting Enzyme Inhibitors

Spontaneous Hinge-Bending Motions of Angiotensin I Converting Enzyme: Role in Activation and Inhibition

Cardiovascular Active Peptides of Marine Origin with ACE Inhibitory Activities: Potential Role as Anti-Hypertensive Drugs and in Prevention of SARS-CoV-2 Infection

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