Dataset Information

Small molecule angiotensin converting enzyme inhibitors: A medicinal chemistry perspective.

ABSTRACT: Angiotensin-converting enzyme (ACE), a zinc metalloprotein, is a central component of the renin-angiotensin system (RAS). It degrades bradykinin and other vasoactive peptides. Angiotensin-converting-enzyme inhibitors (ACE inhibitors, ACEIs) decrease the formation of angiotensin II and increase the level of bradykinin, thus relaxing blood vessels as well as reducing blood volume, lowering blood pressure and reducing oxygen consumption by the heart, which can be used to prevent and treat cardiovascular diseases and kidney diseases. Nevertheless, ACEIs are associated with a range of adverse effects such as renal insufficiency, which limits their use. In recent years, researchers have attempted to reduce the adverse effects of ACEIs by improving the selectivity of ACEIs for structural domains based on conformational relationships, and have developed a series of novel ACEIs. In this review, we have summarized the research advances of ACE inhibitors, focusing on the development sources, design strategies and analysis of structure-activity relationships and the biological activities of ACE inhibitors.

SUBMITTER: Zheng W

PROVIDER: S-EPMC9664202 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Small molecule angiotensin converting enzyme inhibitors: A medicinal chemistry perspective.

Zheng Wenyue W Tian Erkang E Liu Zhen Z Zhou Changhan C Yang Pei P Tian Keyue K Liao Wen W Li Juan J Ren Changyu C

Frontiers in pharmacology 20221101

Angiotensin-converting enzyme (ACE), a zinc metalloprotein, is a central component of the renin-angiotensin system (RAS). It degrades bradykinin and other vasoactive peptides. Angiotensin-converting-enzyme inhibitors (ACE inhibitors, ACEIs) decrease the formation of angiotensin II and increase the level of bradykinin, thus relaxing blood vessels as well as reducing blood volume, lowering blood pressure and reducing oxygen consumption by the heart, which can be used to prevent and treat cardiovas ...[more]

PMID: 36386190

Similar Datasets

Project description:Angiotensin converting enzyme (ACE) is a key enzyme and mediator in the aetiology of high blood pressure (HBP) and hypertension. As one of the leading cause of untimely death worldwide, there is a lot of research and studies on the management and treatment of hypertension. The usage of medicinal plants in the management of hypertension as alternative to synthetic allopathic drugs is a common practice in folkloric and traditional medicine. Therefore, this study was aimed to investigate the ACE inhibitory activity of some medicinal plants which are commonly used in the treatment of HBP in southwestern part of Nigeria using extensive in-silico approach. Compounds identified in the plants through GC-MS technique, together with Lisinopril were docked against ACE protein. It was observed that only 40 of the compounds had binding affinity ≥ - 6.8 kcal/mol which was demonstrated by the standard drug (lisinopril). Interaction between the compounds and ACE was via conventional hydrogen, carbon hydrogen, alkyl, pi-alkyl, pi-carbon, and Van Der Wall bonds among others. Most of these compounds exhibited drug like properties, without violating majority of the physicochemical descriptors and Lipinski rule of 5. The ADMET evaluation revealed that only 2 compounds (cyclopentadecanone and oxacycloheptadecan-2-one) which were identified in Bacopa florinbunda plant were predicted non-toxic and thus were subjected to molecular dynamics and simulation with ACE. From the molecular dynamics and mechanics analysis, both cyclopentadecanone and oxacycloheptadecan-2-one showed high stability and inhibitory potentials when bound to ACE. Oxacycloheptadecan-2-one was more stable than lisinopril and cyclopentadecanone in the ligand-ACE complex; we therefore suggested its experimental and clinical validation as drug candidates for the treatment of hypertension.Supplementary informationThe online version contains supplementary material available at 10.1007/s40203-022-00135-z.

Project description:ImportanceThe renin-angiotensin system has been implicated in mood disorders. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are among the most commonly used medications, yet their effects on mental health outcomes, particularly suicide, are poorly understood. This study examined the association between suicide and exposure to ACEIs and ARBs. Because of differences in their mode of action, it was speculated that ARBs would be associated with a higher risk of suicide than ACEIs.ObjectiveTo examine the association between suicide and exposure to ARBs compared with ACEIs.Design, setting, and participantsThis population-based nested case-control study of individuals aged 66 years and older used administrative claims databases in Ontario, Canada, from January 1, 1995, to December 31, 2015. Data analysis was performed from January to April 2019. Cases were individuals who died by suicide within 100 days of receiving an ACEI or ARB. The date of death served as the index date. For each case, 4 controls were identified and matched by age (within 1 year), sex, and presence of hypertension and diabetes. All individuals received an ACEI or ARB within 100 days before the index date.ExposuresUse of an ACEI or ARB.Main outcomes and measuresConditional logistic regression was used to estimate odds ratios for the association between suicide and exposure to ARBs compared with ACEIs.ResultsNine hundred sixty-four cases were matched to 3856 controls. The median (interquartile range) age of cases and controls was 76 (70-82) years. Most cases (768 [79.7%]) and controls (3068 [79.6%]) were men. Among cases, 260 (26.0%) were exposed to ARBs, and 704 (18.4%) were exposed to ACEIs. Among controls, 741 (74.0%) were exposed to ARBs, and 3115 (81.6%) were exposed to ACEIs. Compared with ACEI exposure, ARB exposure was associated with higher risk of death by suicide (adjusted odds ratio, 1.63; 95% CI, 1.33-2.00). The findings were consistent in a sensitivity analysis excluding individuals with a history of self-harm (odds ratio, 1.60; 95% CI, 1.29-1.98).Conclusions and relevanceThe use of ARBs may be associated with an increased risk of suicide compared with ACEIs. Preferential use of ACEIs over ARBs should be considered whenever possible, particularly in patients with severe mental health illness.

Project description: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.

Project description:BackgroundRenin inhibitors (RIs) reduce blood pressure more than placebo, with the magnitude of this effect thought to be similar to that for angiotensin converting enzyme (ACE) inhibitors. However, a drug's efficacy in lowering blood pressure cannot be considered as a definitive indicator of its effectiveness in reducing mortality and morbidity. The effectiveness and safety of RIs compared to ACE inhibitors in treating hypertension is unknown.ObjectivesTo evaluate the benefits and harms of renin inhibitors compared to ACE inhibitors in people with primary hypertension.Search methodsThe Cochrane Hypertension Group Information Specialist searched the following databases for randomized controlled trials up to August 2020: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers about further published and unpublished work. The searches had no language restrictions.Selection criteriaWe included randomized, active-controlled, double-blinded studies (RCTs) with at least four weeks follow-up in people with primary hypertension, which compared renin inhibitors with ACE inhibitors and reported morbidity, mortality, adverse events or blood pressure outcomes. We excluded people with proven secondary hypertension.Data collection and analysisTwo review authors independently selected the included trials, evaluated the risks of bias and entered the data for analysis.Main resultsWe include 11 RCTs involving 13,627 participants, with a mean baseline age from 51.5 to 74.2 years. Follow-up duration ranged from four weeks to 36.6 months. There was no difference between RIs and ACE inhibitors for the outcomes: all-cause mortality: risk ratio (RR) 1.05, 95% confidence interval (CI) 0.93 to 1.18; 5 RCTs, 5962 participants; low-certainty evidence; total myocardial infarction: RR 0.86, 95% CI 0.22 to 3.39; 2 RCTs, 957 participants; very low-certainty evidence; adverse events: RR 0.98, 95% CI 0.93 to 1.03; 10 RTCs, 6007 participants; moderate-certainty evidence; serious adverse events: RR 1.21, 95% CI 0.89 to 1.64; 10 RTCs, 6007 participants; low-certainty evidence; and withdrawal due to adverse effects: RR 0.85, 95% CI 0.68 to 1.06; 10 RTCs, 6008 participants; low-certainty evidence. No data were available for total cardiovascular events, heart failure, stroke, end-stage renal disease or change in heart rate. Low-certainty evidence suggested that RIs reduced systolic blood pressure: mean difference (MD) -1.72, 95% CI -2.47 to -0.97; 9 RCTs, 5001 participants; and diastolic blood pressure: MD -1.18, 95% CI -1.65 to -0.72; 9 RCTs, 5001 participants, to a greater extent than ACE inhibitors, but we judged this to be more likely due to bias than a true effect. AUTHORS' CONCLUSIONS: For the treatment of hypertension, we have low certainty that renin inhibitors (RI) and angiotensin converting enzyme (ACE) inhibitors do not differ for all-cause mortality and myocardial infarction. We have low to moderate certainty that they do not differ for adverse events. Small reductions in blood pressure with renin inhibitors compared to ACE inhibitors are of low certainty. More independent, large, long-term trials are needed to compare RIs with ACE inhibitors, particularly assessing morbidity and mortality outcomes, but also on blood pressure-lowering effect.

Dataset Information

Small molecule angiotensin converting enzyme inhibitors: A medicinal chemistry perspective.

Publications

Small molecule angiotensin converting enzyme inhibitors: A medicinal chemistry perspective.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets