Considerations for Docking of Selective Angiotensin-Converting Enzyme Inhibitors

Abstract

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.

The Antihypertensive Effects and Potential Molecular Mechanism of Microalgal Angiotensin I-Converting Enzyme Inhibitor-Like Peptides: A Mini Review

“…Great efforts have been made in recent years in the molecular docking of biopeptides from conventional foods to ACE [ 82 , 83 ]. However, unlike ACE inhibitor-like peptides from traditional food sources, the molecular interaction mechanism and molecular docking of microalgal peptides are still untapped.…”

Computational Modeling to Explain Why 5,5-Diarylpentadienamides are TRPV1 Antagonists

“…The LigRMSD results found when comparing the positions of the congeneric ligands or their identical or similar fragments show a more detailed analysis that confirmed the similar orientation of the studied compounds obtained via the docking protocol used in this work. Another part of the analysis consisted of the annotation of the recurrent interactions that were observed between the docked ligands and the TRPV1 binding site, which was carried out by computing the interaction fingerprints (IFPs) [22,23]. In general, despite the differences noted between the binding poses of the compounds from series A and B, the neck pentadienamide group was placed at the same position for the whole set, with RMSD values below 1.3 Å.…”

Exacerbation of COVID 19 in Hypertensive Patients ( A review)

“…Aldosterone is another biomolecule that affecting the body homeostasis, which play an important role in the reabsorption of sodium ions, potassium excretion, and water retention from the distal nephrons of the kidney, by that modulate the extracellular space volume and blood pressure (26) . Angiotensin Converting Enzyme (ACE) is a membrane bounded glycoprotein, which play an important role in the blood pressure homeostasis, through negative modulation of Renin-Angiotensin Aldosterone System (RAAS) converting of Angiotensin I into Angiotensin II, which is potent vasoconstrictor that associated with elevation in blood pressure (27) . Due to the vital role of these biomolecules in regulation of body homeostasis, therefore most patients with elevating blood pressure, and cardiovascular diseases are treated with Angiotensin Receptor Blockers (ARBs), and Angiotensin Converting Enzyme Inhibitors (ACE-I) (28) , a major concern was raised about the safety and/ or persistent beneficial effects of these drugs in SARS-COVID-19 infected patients (29) .…”