Molecular insights into the interaction of hemorphin and its targets

Ali, Amanat; Baby, Bincy; Soman, Soja Saghar; Vijayan, Ranjit

doi:10.1038/s41598-019-50619-w

Cited by 25 publications

(17 citation statements)

References 84 publications

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“…A number of studies have highlighted their therapeutic potential [10,[17][18][19]47,48]. We had previously reported the molecular binding behavior of camel and non-camel LVV-hemorphin-7 on multiple targets [20,25]. Here, we report the binding and ACE inhibition potential of non-camel hemorphins (LVVYPWTQRF and YPWTQRF) and camel hemorphins (LVVYPWTRRF and YPWTRRF) using computational approaches and an in vitro ACE inhibition assay.…”

Section: Discussionmentioning

confidence: 95%

“…The sequence of hemorphin peptide is highly conserved in mammals, which suggests similar biological activities in different mammals under different conditions. However, the camel hemorphin (LVVYPWTRRF) harbors a Q>R variation [25]. Camels have unique genetic adaptations that permit it to survive severe dehydration and very harsh environmental conditions [26,27].…”

Section: Introductionmentioning

confidence: 99%

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Camel Hemorphins Exhibit a More Potent Angiotensin-I Converting Enzyme Inhibitory Activity than Other Mammalian Hemorphins: An In Silico and In Vitro Study

et al. 2020

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Angiotensin-I converting enzyme (ACE) is a zinc metallopeptidase that has an important role in regulating the renin-angiotensin-aldosterone system (RAAS). It is also an important drug target for the management of cardiovascular diseases. Hemorphins are endogenous peptides that are produced by proteolytic cleavage of beta hemoglobin. A number of studies have reported various therapeutic activities of hemorphins. Previous reports have shown antihypertensive action of hemorphins via the inhibition of ACE. The sequence of hemorphins is highly conserved among mammals, except in camels, which harbors a unique Q>R variation in the peptide. Here, we studied the ACE inhibitory activity of camel hemorphins (LVVYPWTRRF and YPWTRRF) and non-camel hemorphins (LVVYPWTQRF and YPWTQRF). Computational methods were used to determine the most likely binding pose and binding affinity of both camel and non-camel hemorphins within the active site of ACE. Molecular dynamics simulations showed that the peptides interacted with critical residues in the active site of ACE. Notably, camel hemorphins showed higher binding affinity and sustained interactions with all three subsites of the ACE active site. An in vitro ACE inhibition assay showed that the IC50 of camel hemorphins were significantly lower than the IC50 of non-camel hemorphins.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Camel Hemorphins Exhibit a More Potent Angiotensin-I Converting Enzyme Inhibitory Activity than Other Mammalian Hemorphins: An In Silico and In Vitro Study

et al. 2020

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“…Other recent works on the identification of natural peptides are mentioned here: Ali et al [26] investigated the most likely binding poses of the decapeptide LVV-hemorphin-7 (which is the most stable form of hemorphin) with three biological targets, including ACE. They studied mammalian and camel LVV-hemorphin-7 and used computational methods (including docking and MM/GBSA) to calculate the binding affinities, and MD to gain a better understanding of the dynamics of the molecular interactions between the selected targets and hemorphin peptides.…”

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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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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“…Ali et al presented computational methods to elucidate the alignment of mammalian LVV-H7 to mu-opioid receptors (MOR), angiotensin-converting enzyme (ACE) and insulinregulated aminopeptidase (IRAP) that are its binding counterparts, and to calculate the binding affinity to these proteins [55]. It was shown that camel LVV-H7 produced stronger interactions with all studied proteins (MOR, ACE and IRAP) than non-camel LVV-H7.…”

Section: Other Techniquesmentioning

confidence: 99%

Hemorphins—From Discovery to Functions and Pharmacology

et al. 2021

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During the last three decades, a variety of different studies on bioactive peptides that are opioid receptor ligands, have been carried out, with regard to their isolation and identification, as well as their molecular functions in living organisms. Thus, in this review, we would like to summarize the present state-of-the art concerning hemorphins, methodological aspects of their identification, and their potential role as therapeutic agents. We have collected and discussed articles describing hemorphins, from their discovery up until now, thus presenting a very wide spectrum of their characteristic and applications. One of the major assets of the present paper is a combination of analytical and pharmacological aspects of peptides described by a team who participated in the initial research on hemorphins. This review is, in part, focused on the analysis of endogenous opioid peptides in biological samples using advanced techniques, description of the identification of synthetic/endogenous hemorphins, their involvement in pharmacology, learning, pain and other function. Finally, the part regarding hemorphin analogues and their synthesis, has been added.

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Molecular insights into the interaction of hemorphin and its targets

Cited by 25 publications

References 84 publications

Camel Hemorphins Exhibit a More Potent Angiotensin-I Converting Enzyme Inhibitory Activity than Other Mammalian Hemorphins: An In Silico and In Vitro Study

Camel Hemorphins Exhibit a More Potent Angiotensin-I Converting Enzyme Inhibitory Activity than Other Mammalian Hemorphins: An In Silico and In Vitro Study

Considerations for Docking of Selective Angiotensin-Converting Enzyme Inhibitors

Hemorphins—From Discovery to Functions and Pharmacology

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