Carvedilol serves as a novel CYP1B1 inhibitor, a systematic drug repurposing approach through structure-based virtual screening and experimental verification

Wang, Ying; He, Xiaomei; Li, Chunshi; Ma, Yan; Xue, Wenchi; Hu, Baichun; Wang, Jian; Zhang, Tingting; Zhang, Fengjiao

doi:10.1016/j.ejmech.2020.112235

Cited by 34 publications

(21 citation statements)

References 33 publications

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“…Another way to search for efficient and selective CYP1B1 inhibitors is the structurebased virtual screening of approved drugs registered in the FDA database, which Wang and his group applied. The screening results were correlated with experimental determination of inhibitory activity, indicating beta-blocker carvedilol (Figure 6) as a promising CYP1B1 inhibitor [98]. Carvedilol, a drug used in the treatment of high blood pressure and heart failure, was docked to the X-ray crystal structure of the enzyme (PDB code: 6IQ5).…”

Section: Design Of Selective Cyp1b1 Inhibitorsmentioning

confidence: 75%

“…Its binding pose in the CYP1B1 cavity was stabilized by π-π stacking interaction formed by a 9H-carbazole group of carvedilol with Phe231. As in other cases of CYP1B1 inhibitors, hydrophobic interactions formed by the methoxy-substituted phenyl with heme and surrounding residues decided on the affinity of carvedilol to the CYP1B1 binding site [98].…”

Section: Design Of Selective Cyp1b1 Inhibitorsmentioning

confidence: 87%

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New Perspectives of CYP1B1 Inhibitors in the Light of Molecular Studies

Mikstacka

Dutkiewicz

2021

Processes

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Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic heme-containing monooxygenase. CYP1B1 contributes to the oxidative metabolism of xenobiotics, drugs, and endogenous substrates like melatonin, fatty acids, steroid hormones, and retinoids, which are involved in diverse critical cellular functions. CYP1B1 plays an important role in the pathogenesis of cardiovascular diseases, hormone-related cancers and is responsible for anti-cancer drug resistance. Inhibition of CYP1B1 activity is considered as an approach in cancer chemoprevention and cancer chemotherapy. CYP1B1 can activate anti-cancer prodrugs in tumor cells which display overexpression of CYP1B1 in comparison to normal cells. CYP1B1 involvement in carcinogenesis and cancer progression encourages investigation of CYP1B1 interactions with its ligands: substrates and inhibitors. Computational methods, with a simulation of molecular dynamics (MD), allow the observation of molecular interactions at the binding site of CYP1B1, which are essential in relation to the enzyme’s functions.

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Section: Design Of Selective Cyp1b1 Inhibitorsmentioning

confidence: 75%

Section: Design Of Selective Cyp1b1 Inhibitorsmentioning

confidence: 87%

New Perspectives of CYP1B1 Inhibitors in the Light of Molecular Studies

Mikstacka

Dutkiewicz

2021

Processes

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“…Intriguingly, the anti-fungal drug fluconazole has been shown to inhibit CYP1B1 and protect against angiotensin II-induced cardiac hypertrophy [152]. Similarly, the clinically relevant β-blocker carvedilol has been found to inhibit CYP1B1 through a systematic drug repurposing approach [153]. Metformin, a medication usually given to treat diabetes, has also been shown to inhibit CYP1B1 expression, specifically in breast cancer cells [154].…”

Section: Cyp1b1 Inhibitorsmentioning

confidence: 99%

CYP1B1 as a therapeutic target in cardio-oncology

2020

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Cardiovascular complications have been frequently reported in cancer patients and survivors, mainly because of various cardiotoxic cancer treatments. Despite the known cardiovascular toxic effects of these treatments, they are still clinically used because of their effectiveness as anti-cancer agents. In this review, we discuss the growing body of evidence suggesting that inhibition of the cytochrome P450 1B1 enzyme (CYP1B1) can be a promising therapeutic strategy that has the potential to prevent cancer treatment-induced cardiovascular complications without reducing their anti-cancer effects. CYP1B1 is an extrahepatic enzyme that is expressed in cardiovascular tissues and overexpressed in different types of cancers. A growing body of evidence is demonstrating a detrimental role of CYP1B1 in both cardiovascular diseases and cancer, via perturbed metabolism of endogenous compounds, production of carcinogenic metabolites, DNA adduct formation, and generation of reactive oxygen species (ROS). Several chemotherapeutic agents have been shown to induce CYP1B1 in cardiovascular and cancer cells, possibly via activating the Aryl hydrocarbon Receptor (AhR), ROS generation, and inflammatory cytokines. Induction of CYP1B1 is detrimental in many ways. First, it can induce or exacerbate cancer treatment-induced cardiovascular complications. Second, it may lead to significant chemo/radio-resistance, undermining both the safety and effectiveness of cancer treatments. Therefore, numerous preclinical studies demonstrate that inhibition of CYP1B1 protects against chemotherapy-induced cardiotoxicity and prevents chemo- and radio-resistance. Most of these studies have utilized phytochemicals to inhibit CYP1B1. Since phytochemicals have multiple targets, future studies are needed to discern the specific contribution of CYP1B1 to the cardioprotective and chemo/radio-sensitizing effects of these phytochemicals.

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“…Molecular docking has been proved to be an efficient strategy to speed up the process of drug discovery (da Silva Rocha et al., 2019). Indeed, it is an effective strategy in structure‐based virtual screening considering that it has already yielded numerous bioactive structures toward diverse targets (Wang et al., 2020). In light of this, molecular docking was performed to identify more effective of α‐amylase inhibitors from the MFH plants.…”

Section: Resultsmentioning

confidence: 99%

“…Virtual screening is an indispensable technique that has great importance in the field of drug discovery. It is advised as an alternative method for experimental screening and has a significant success rate in the drug discovery process (Park et al., 2008; Shen et al., 2012; Wang et al., 2020). It can help in the reduction of the immense virtual chemical space of small organic molecules to a manageable number of compounds.…”

Section: Introductionmentioning

confidence: 99%

Screening and identifying of α‐amylase inhibitors from medicine food homology plants: Insights from computational analysis and experimental studies

et al. 2020

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There is a growing interest in screening α-amylase inhibitors from natural products for application in the development of new antidiabetic drugs or functional foods. In this study, a structure-based virtual screening was applied to rapidly identify the α-amylase inhibitors from medicine food homology (MFH) plants. Similarity search, docking & scoring were used for further filter small molecules. As a result, 21 corresponding potential α-amylase inhibitors from MFH plants were obtained. And, six polyphenol compounds (curcumin, procyanidins, epicatechin gallate (ECG), epigallocatechin gallate (EGCG), hesperidin, and puerarin) were highlighted for further verification after a thorough assessment of the classification of hit molecules as well as docking scores. The results of the enzyme inhibition test showed that ECG, EGCG, and procyanidins had the better binding ability of α-amylase among these six polyphenols. The Ki values of ECG, EGCG, and procyanidins on α-amylase were 0.70, 1.68, and 0.24, respectively. The CD spectra results indicated that the three polyphenols can cause conformational changes in α-amylase.

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Carvedilol serves as a novel CYP1B1 inhibitor, a systematic drug repurposing approach through structure-based virtual screening and experimental verification

Cited by 34 publications

References 33 publications

New Perspectives of CYP1B1 Inhibitors in the Light of Molecular Studies

New Perspectives of CYP1B1 Inhibitors in the Light of Molecular Studies

CYP1B1 as a therapeutic target in cardio-oncology

Screening and identifying of α‐amylase inhibitors from medicine food homology plants: Insights from computational analysis and experimental studies

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