Small molecule angiotensin converting enzyme inhibitors: A medicinal chemistry perspective

Zheng, Wenyue; Tian, Erkang; Liu, Zhen; Zhou, Changhan; Yang, Pei; Tian, Keyue; Liao, Wen; Li, Juan; Ren, Chang E.

doi:10.3389/fphar.2022.968104

Cited by 15 publications

(16 citation statements)

References 162 publications

(230 reference statements)

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“…A pivotal discovery relating to the RAS, was the development of captopril, the first ACE inhibitor (ACE-I) drug in 1975 ( Zheng et al, 2022 ). Captopril selectively targets ACE by binding to its active site and preventing the formation of Ang II thereby inhibiting the RAS.…”

Section: Introductionmentioning

confidence: 99%

“…Captopril selectively targets ACE by binding to its active site and preventing the formation of Ang II thereby inhibiting the RAS. It marked a significant milestone in the treatment of hypertension paving the way for the development of additional ACE-Is with improved activity and bioavailability ( Zheng et al, 2022 ). In addition, a new class of drugs known as angiotensin receptor blockers (ARBs), which selectively inhibit Ang II by competitive antagonism of the AT1Rs, were also developed ( Barreras and Gurk-Turner, 2003 ).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, a new class of drugs known as angiotensin receptor blockers (ARBs), which selectively inhibit Ang II by competitive antagonism of the AT1Rs, were also developed ( Barreras and Gurk-Turner, 2003 ). These drugs have proven to be clinically relevant in the treatment of various cardiovascular conditions, including hypertension, heart failure, diabetic nephropathy and continue to be an important therapeutic option for patients today ( Barreras and Gurk-Turner, 2003 ; Zheng et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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Deciphering mechanisms of action of ACE inhibitors in neurodegeneration using Drosophila models of Alzheimer’s disease

Ghalayini

Boulianne

2023

Front. Neurosci.

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Alzheimer’s disease (AD) is a devastating neurodegenerative disorder for which there is no cure. Recently, several studies have reported a significant reduction in the incidence and progression of dementia among some patients receiving antihypertensive medications such as angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs). Why these drugs are beneficial in some AD patients and not others is unclear although it has been shown to be independent of their role in regulating blood pressure. Given the enormous and immediate potential of ACE-Is and ARBs for AD therapeutics it is imperative that we understand how they function. Recently, studies have shown that ACE-Is and ARBs, which target the renin angiotensin system in mammals, are also effective in suppressing neuronal cell death and memory defects in Drosophila models of AD despite the fact that this pathway is not conserved in flies. This suggests that the beneficial effects of these drugs may be mediated by distinct and as yet, identified mechanisms. Here, we discuss how the short lifespan and ease of genetic manipulations available in Drosophila provide us with a unique and unparalleled opportunity to rapidly identify the targets of ACE-Is and ARBs and evaluate their therapeutic effectiveness in robust models of AD.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Deciphering mechanisms of action of ACE inhibitors in neurodegeneration using Drosophila models of Alzheimer’s disease

Ghalayini

Boulianne

2023

Front. Neurosci.

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“…Lisinopril is capable of forming a hydrogen bond with E384 and Y283, establishing a salt bridge with E162 and D377, and engaging in hydrophobic interactions with K511, Q281, and Y520 of the ACE zinc-coordinating residues, as evidenced by crystal structures. 4 According to available sources, ACEIs can be categorized into two groups: synthetic ACEIs from artificial chemical synthesis and natural product ACEIs, derived from natural sources, particularly medicinal plants. 4 Quantitative structure−activity/property relationship (QSAR/QSPR) represents an in silico mathematical model used for predicting the bioactivities or properties of compounds based on their structures and physicochemical parameters.…”

Section: Introductionmentioning

confidence: 99%

“…4 According to available sources, ACEIs can be categorized into two groups: synthetic ACEIs from artificial chemical synthesis and natural product ACEIs, derived from natural sources, particularly medicinal plants. 4 Quantitative structure−activity/property relationship (QSAR/QSPR) represents an in silico mathematical model used for predicting the bioactivities or properties of compounds based on their structures and physicochemical parameters. 5,6 QSAR/QSPR is fundamentally based on two key principles: (i) the structure of a compound determines its bioactivity/property and (ii) compounds with more similar structures exhibit more similar bioactivities or properties.…”

Section: Introductionmentioning

confidence: 99%

Machine Learning Approaches to Investigate the Structure–Activity Relationship of Angiotensin-Converting Enzyme Inhibitors

Yu,

Nantasenamat,

Anuwongcharoen

et al. 2023

ACS Omega

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Angiotensin-converting enzyme inhibitors (ACEIs) play a crucial role in treating conditions such as hypertension, heart failure, and kidney diseases. Nevertheless, the ACEIs currently available on the market are linked to a variety of adverse effects including renal insufficiency, which restricts their usage. There is thus an urgent need to optimize the currently available ACEIs. This study represents a structure−activity relationship investigation of ACEIs, employing machine learning to analyze data sets sourced from the ChEMBL database. Exploratory data analysis was performed to visualize the physicochemical properties of compounds by investigating the distributions, patterns, and statistical significance among the different bioactivity groups. Further scaffold analysis has identified 9 representative Murcko scaffolds with frequencies ≥10. Scaffold diversity has revealed that active ACEIs had more scaffold diversity than their intermediate and inactive counterparts, thereby indicating the significance of performing lead optimization on scaffolds of active ACEIs. Scaffolds 1, 3, 6, and 8 are unfavorable in comparison with scaffolds 2, 3, 5, 7, and 9. QSAR investigation of compiled data sets consisting of 549 compounds led to the selection of Mordred descriptor and Random Forest algorithm as the best model, which afforded robust model performance (accuracy: 0.981, 0.77, and 0.745; MCC: 0.972, 0.658, and 0.617 for the training set, 10-fold cross-validation set, and testing set, respectively). To enhance the model's robustness and predictability, we reduced the chemical diversity of the input compounds by using the 9 most prevalent Murcko scaffold-matched compounds (comprising a total of 168) followed by a subsequent QSAR model investigation using Mordred descriptor and extremely gradient boost algorithm (accuracy: 0.973, 0.849, and 0.823; MCC: 0.959, 0.786, and 0.742 for the training set, 10-fold cross-validation set, and testing set, respectively). Further illustration of the structure− activity relationship using SALI plots has enabled the identification of clusters of compounds that create activity cliffs. These findings, as presented in this study, contribute to the advancement of drug discovery and the optimization of ACEIs.

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New oxadiazol‐5‐ones derivatives and their performance as angiotensin‐converting enzyme (ACE) inhibitors

Ferreira,

Lins,

Feitosa

et al. 2024

Journal of Heterocyclic Chem

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Angiotensin‐converting enzyme inhibitors are widely used in treating arterial hypertension, acting on the renin‐angiotensin‐aldosterone system and controlling blood pressure. We present a novel, greener, and faster methodology to assess the 1,2,4‐oxadiazol‐5‐one ring and perform molecular modifications to obtain angiotensin‐converting enzyme (ACE) inhibitors using this heterocyclic core. Molecular docking simulations indicate that the tested compounds exhibited an affinity for the ACE binding site, with scores comparable to the commercial inhibitor lisinopril. However, in vitro assays revealed that the compounds were ineffective in inhibiting ACE activity. The lack of inhibition may be related to the compounds' more apolar nature. These results emphasize the importance of integrating computational and experimental approaches in developing new drugs, providing valuable insights for planning future studies to optimize the activity of synthesized compounds.

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Small molecule angiotensin converting enzyme inhibitors: A medicinal chemistry perspective

Cited by 15 publications

References 162 publications

Deciphering mechanisms of action of ACE inhibitors in neurodegeneration using Drosophila models of Alzheimer’s disease

Deciphering mechanisms of action of ACE inhibitors in neurodegeneration using Drosophila models of Alzheimer’s disease

Machine Learning Approaches to Investigate the Structure–Activity Relationship of Angiotensin-Converting Enzyme Inhibitors

New oxadiazol‐5‐ones derivatives and their performance as angiotensin‐converting enzyme (ACE) inhibitors

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