Pharmacophore Modeling and in Silico/in Vitro Screening for Human Cytochrome P450 11B1 and Cytochrome P450 11B2 Inhibitors

Akram, Muhammad; Waratchareeyakul, Watcharee; Haupenthal, Jörg; Hartmann, Rolf W.; Schuster, Daniela

doi:10.3389/fchem.2017.00104

Cited by 19 publications

(7 citation statements)

References 83 publications

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“…Pharmacophore modeling and subsequent virtual screening (VS) is a well-established method in the early drug discovery process showing some important benefits: (1) pharmacophore screening can retrieve ligands with structurally diverse scaffolds and allows for so called “scaffold-hopping”; (2) it can automatically and rapidly filter large compound libraries; (3) ligand-based pharmacophore VS has been able to retrieve satisfactory results, also without structural information on the target (Evers et al, 2005 ; Ha et al, 2015 ; Akram et al, 2017 ). Here, we report on the construction of two ligand-based 3D pharmacophore models, their in silico and in vitro validation, and the directed discovery of sesquiterpene coumarins as a new class of potent GPBAR1 agonists.…”

Section: Introductionmentioning

confidence: 99%

In Silico Workflow for the Discovery of Natural Products Activating the G Protein-Coupled Bile Acid Receptor 1

et al. 2018

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The G protein-coupled bile acid receptor (GPBAR1) has been recognized as a promising new target for the treatment of diverse diseases, including obesity, type 2 diabetes, fatty liver disease and atherosclerosis. The identification of novel and potent GPBAR1 agonists is highly relevant, as these diseases are on the rise and pharmacological unmet therapeutic needs are pervasive. Therefore, the aim of this study was to develop a proficient workflow for the in silico prediction of GPBAR1 activating compounds, primarily from natural sources. A protocol was set up, starting with a comprehensive collection of structural information of known ligands. This information was used to generate ligand-based pharmacophore models in LigandScout 4.08 Advanced. After theoretical validation, the two most promising models, namely BAMS22 and TTM8, were employed as queries for the virtual screening of natural product and synthetic small molecule databases. Virtual hits were progressed to shape matching experiments and physicochemical clustering. Out of 33 diverse virtual hits subjected to experimental testing using a reporter gene-based assay, two natural products, farnesiferol B (27) and microlobidene (28), were confirmed as GPBAR1 activators reaching more than 50% receptor activation at 20 μM with EC50s of 13.53 μM and 13.88 μM, respectively. This activity is comparable to that of the endogenous ligand lithocholic acid (1). Seven further virtual hits showed activity reaching at least 15% receptor activation either at 5 or 20 μM, including new scaffolds from natural and synthetic origin.

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Section: Introductionmentioning

confidence: 99%

In Silico Workflow for the Discovery of Natural Products Activating the G Protein-Coupled Bile Acid Receptor 1

et al. 2018

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“…Additionally, we considered the molecular mechanism of the treatment that was used as medicine in this study. The CYP11B1 and CYP11B2 enzymes belong to the cytochrome P450 family of enzymes and are involved in the synthesis of adrenocortical hormones [27]. CYP11B1 is located in the adrenal zona fasciculata and is involved in the synthesis of corticosterone, whereas CYP11B2 is located in the adrenal zona glomerulosa and is involved in aldosterone synthesis [27].…”

Section: Discussionmentioning

confidence: 99%

“…The CYP11B1 and CYP11B2 enzymes belong to the cytochrome P450 family of enzymes and are involved in the synthesis of adrenocortical hormones [27]. CYP11B1 is located in the adrenal zona fasciculata and is involved in the synthesis of corticosterone, whereas CYP11B2 is located in the adrenal zona glomerulosa and is involved in aldosterone synthesis [27]. The expression of CYP11B1 has been shown to be increased by stimulation with ACTH, whereas the expression of CYP11B2 has been shown to increase with sodium loss and to decrease with prolonged ACTH stimulation [28].…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid Receptor Antagonist Administration Prevents Adrenal Gland Atrophy in an ACTH-Independent Cushing’s Syndrome Rat Model

Yasuda

Seki

Kametani

et al. 2019

International Journal of Endocrinology

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ACTH-independent Cushing’s syndrome (CS) is mainly caused by cortisol-secreting adrenocortical tumours. It is well known that secondary adrenal insufficiency occurs after surgical resection of these tumours. In this regard, impaired adrenocortical function is likely induced by atrophy of the residual adrenal tissue as a result of chronic suppression by the low ACTH levels of the hypercortisolism state. Therefore, we considered the prevention of adrenal atrophy as a method for preventing postoperative adrenal insufficiency. On the basis of these findings, we hypothesized that the use of a glucocorticoid receptor (GR) antagonist before surgery in ACTH-independent CS would rapidly activate the hypothalamic-pituitary-adrenal (HPA) axis and residual adrenal function. We thus examined adrenal function in a dexamethasone- (DEX-) induced CS rat model with or without mifepristone (MIF). In this study, MIF-treated rats had elevated plasma ACTH levels and increased adrenal weights. In addition, we confirmed that there were fewer atrophic changes, as measured by the pathological findings and mRNA expression levels of corticosterone synthase CYP11B1 in the adrenal glands, in MIF-treated rats. These results indicate that MIF treatment prevents the suppression of the HPA axis and the atrophy of the residual adrenal tissue. Therefore, our study suggests that preoperative GR antagonist administration may improve residual adrenal function and prevent postoperative adrenal insufficiency in ACTH-independent CS.

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“…It was later termed COVID-19 pandemic disease by the World Health Organisation (WHO) [1], the situation of which threatens the global health, economy and population severely through daily loss of lives, leading to its further declaration as public health emergency of international concern by WHO in January, 2020 [1,2]. The death rate of COVID-19 as of 27 th August, 2020 stands at 5.0% with 24,331,524 of the global population con rmed infected out of which 16,872,542 patients have recovered and 829,664 [3][4][5]. The infants and aged population with weak immune systems as well as individuals suffering from co-existing complications of other ailments such as cardiovascular diseases, myocardial injury, hypertension, in uenza, diabetes, pneumonia etc are more vulnerable [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Identification of Multi-Target Directed Inhibitors of SARS-CoV-2: Drug Repurposing

Ayipo

Alananzeh

Sani

et al. 2021

Preprint

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Background: COVID-19 remains a major global challenge while several drugs identified to ameliorate the syndromes are associated with incessant resistance and lack of prospective potentials to permanently curb the infection. This study is aimed at evaluating the potentials of the existing drug molecules to overcome the viral resistance through multi-target inhibition mechanisms. Methods: Molecular docking and molecular dynamics simulations have been extensively applied to virtually screen 2826 drugs from Selleckem.com library against some key bio-receptors implicated in the SARS-CoV-2 such as the viral nucleocapsid phosphoprotein, the viral spike glycoprotein and the human host ACE2. Results: Five drugs namely D-(+)-Raffinose pentahydrate (1), (-)-Epicatechin gallate (5), 2797 (7), Rutin DAB10 (8) and Hyperoside (9) display higher inhibitory potentials against N-terminal NTD of SARS-CoV-2 (PDB 6M3M) with XP docking scores of -16.20, -11.98, -11.83, -11.81 and -11.41 than remdesivir and ribavirin with -10.27 and -9.06 respectively. Their estimated binding free energies against the receptor are -27.80, -27.91, -32.39, -27.91 and -29.50 kcal/mol compared to remdesivir and ribavirin with -24.27 and -15.37 kcal/mol respectively. Similar inhibition patterns were observed against the viral S-protein and the human ACE2 with high stability and bio-functionality. Conclusion: The identified compounds show promising potentials amenable for breakthrough against the drug-resistant COVID-19 upon further studies.

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Pharmacophore Modeling and in Silico/in Vitro Screening for Human Cytochrome P450 11B1 and Cytochrome P450 11B2 Inhibitors

Cited by 19 publications

References 83 publications

In Silico Workflow for the Discovery of Natural Products Activating the G Protein-Coupled Bile Acid Receptor 1

In Silico Workflow for the Discovery of Natural Products Activating the G Protein-Coupled Bile Acid Receptor 1

Glucocorticoid Receptor Antagonist Administration Prevents Adrenal Gland Atrophy in an ACTH-Independent Cushing’s Syndrome Rat Model

Identification of Multi-Target Directed Inhibitors of SARS-CoV-2: Drug Repurposing

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