The Computational Interaction Analyses of Some Vitamin D-Related Compounds with Sterol 14-Demethylase (CYP51) – Could It Be a Glimmer of Hope to Find New Anti-Mucormycotic Drugs Extracted from Plants-Derived Sterols?

Author: Almutairi, Majed Meshal ; Althaiban, Abdullah K. ; Alsubhi, Wael A. ; Al-Mazaideh, Ghassab M. ; Faris Shalayel, Mohammed Helmy

Introduction Many vitamin D analogs and sterols-related compounds have been identified and extracted from several plants including Solanaceae species. The aim of our study was to evaluate the antifungal potential of 15 vitamin D, D3 analogs, and some sterols-related compounds that have been detected in some plants along with 3 standard antifungal drugs, Isavuconazole, Fluconazole, and Voriconazole, on the Mucormycosis-sterol 14-alpha demethylase (CYP51) enzyme by in silico study. Methods In this work, the molecular simulation was used to prepare the specific enzyme and the antifungal profiles utilized for the molecular docking of the contemplated compounds and subsequent prediction for the mechanism of binding within the catalytic site of Sterol 14-Demethylase (CYP51) to speculate their binding affinities. Anti-fungal medications, Fluconazole and Voriconazole revealed drugs bound distant from the binding sites, but Isavuconazole bound close to the binding site. In this context, the 15 vitamin D and D3 compounds were somewhat seen in binding proximity, especially for Alfacalcidol, Eldecalcitol, and Inecalcitol. Results Seocalcitol and Isavuconazole had the lowest binding energies and were the closest ones connected to the binding cavities with the best binding free energies equal −13.21 ± 0.24 and −15.29 ± 0.25, respectively. Conclusion Isavuconazole and Seocalcitol could potentially be further assessed to be adjuvantly used as drugs to inhibit the fungal activity by targeting CYP51, a significant target for anti-fungal as well as anti-protozoan drugs, and hence could be efficient against mucormycosis.

01 Jan 2023·Environmental Research

The vitamin D receptor as a potential target for the toxic effects of per- and polyfluoroalkyl substances (PFASs): An in-silico study

Article

Author: Furlow, J David ; Wang, Jen-Chywan ; Azhagiya Singam, Ettayapuram Ramaprasad ; Smith, Martyn T ; La Merrill, Michele A ; Durkin, Kathleen A

Due to their persistence and toxicity, perfluoroalkyl and polyfluoroalkyl substances (PFASs) constitute significant hazards to human health and the environment. Their effects include immune suppression, altered hormone levels, and osteoporosis. Recently, the most studied PFAS, perfluorooctanoic acid (PFOA), was shown to competitively binding to the Vitamin D receptor (VDR). VDR plays a crucial role in regulating genes involved in maintaining immune, endocrine, and calcium homeostasis, suggesting it may be a target for at least some of the health effects of PFAS. Hence, this study examined the potential binding of 5206 PFASs to VDR using molecular docking, molecular dynamics, and free energy binding calculations. We identified 14 PFAS that are predicted to interact strongly with VDR, similar to the natural ligands. We further investigated the interactions of VDR with 256 PFASs of established commercial importance. Eighty-three (32%) of these 256 commercially important PFAS were predicted to be stronger binders to VDR than PFOA. At least 16 PFASs of regulatory importance, because they have been identified in water supplies and human blood samples, were also more potent binders to VDR than PFOA. Further, PFASs are usually found together in contaminated drinking water and human blood samples, which raises the concern that multiple PFASs may act together as a mixture on VDR function, potentially producing harmful effects on the immune, endocrine, and bone homeostasis.

01 Dec 2021·BMC NephrologyQ4 · MEDICINE

Bone responsiveness to parathyroid hormone is negatively associated with parathyroid hormone-lowering drug use in patients undergoing hemodialysis: a cross-sectional study

Q4 · MEDICINE

ArticleOA

Author: Sumi, Hirofumi ; Tominaga, Naoto ; Shibagaki, Yugo ; Yano, Shozo ; Yamanouchi, Masayuki ; Shiizaki, Kazuhiro ; Yonaha, Tomoki ; Taki, Yasuhiro

AbstractBackgroundParathyroid hormone (PTH) acts on bone to indirectly increase the number and activity of osteoclasts. Thus, PTH has a stimulatory effect on bone resorption and upregulates bone turnover. However, the responsiveness of bone to PTH varies widely among patients receiving dialysis. In fact, relative to the serum PTH level, the level of serum tartrate-resistant acid phosphatase-5b (TRACP-5b), a bone resorption marker derived from osteoclasts, varies as well. This study aimed to examine factors related to bone responsiveness to PTH in patients undergoing chronic hemodialysis (HD).MethodsThis study included patients receiving chronic HD in Kawasaki Municipal Tama Hospital (Kanagawa, Japan) and Yonaha Medical Clinic (Okinawa, Japan) and excluded patients who received HD for less than 6 months, those who received a combination of HD and peritoneal dialysis, and those who had cancer bone metastases or myeloma. The TRACP-5b/intact PTH (iPTH) ratio was created as an index of bone responsiveness to PTH, categorized into tertiles (low, medium, and high), and a cross-sectional study was conducted. P < 0.05 indicated statistically significant differences.ResultsOne hundred and six patients were analyzed. Age (P = 0.010), body mass index (BMI) (P = 0.003), use of calcium-sensing receptor (CaSR) agonists (P = 0.008), use of vitamin D receptor activators (VDRAs) (P = 0.012), plasma iPTH level (P < 0.001), serum 1,25(OH)2D level (P = 0.003), and serum TRACP-5b level (P < 0.001) were significantly different among the three categories. In the single linear regression analysis, age (P = 0.016), corrected serum calcium level (P = 0.007), and ln [1,25(OH)2D] (P = 0.044) showed a significant positive correlation with ln [TRACP-5b/iPTH], whereas BMI (P = 0.026), use of CaSR agonists (P = 0.001), use of VDRAs (P = 0.009), and serum phosphorus level (P = 0.018) showed a significant negative correlation. Upon conducting multiple linear regression analysis incorporating significant variables in the single linear regression analysis, a significant negative correlation was observed between the TRACP-5b/iPTH ratio and intravenous administration of a CaSR agonist (etelcalcetide) and/or a VDRA (calcitriol or maxacalcitol) in all the adjusted models.ConclusionsBone responsiveness to PTH is negatively correlated with the intravenous administration of a CaSR agonist and/or a VDRA in patients undergoing chronic HD.

100 Deals associated with Falecalcitriol

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KEGG	Wiki	ATC	Drug Bank
D01662	Falecalcitriol	A11CC	-

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Hyperparathyroidism	Japan	Sumitomo Pharma Co., Ltd.	04 Apr 2001
Hyperparathyroidism, Secondary	Japan	Kissei Pharmaceutical Co., Ltd.	01 Apr 2001
Hypoparathyroidism	Japan	Kissei Pharmaceutical Co., Ltd.	01 Apr 2001
Osteomalacia	Japan	Kissei Pharmaceutical Co., Ltd.	01 Apr 2001
Rickets	Japan	Kissei Pharmaceutical Co., Ltd.	01 Apr 2001

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Osteoporosis, Postmenopausal	Preclinical	United States	Windtree Therapeutics, Inc.	08 Dec 1997
Osteoporosis, Postmenopausal	Preclinical	United States	Windtree Therapeutics, Inc.	08 Dec 1997
Well Aging	Preclinical	United States	Penederm, Inc.	05 Jun 1997
Acne Vulgaris	Preclinical	United States	Mylan Bertek Pharmaceuticals, Inc.	-
Kidney Diseases	Preclinical	Japan	Taisho Pharmaceutical Co., Ltd.	-
Photodamaged skin	Preclinical	United States	Mylan Bertek Pharmaceuticals, Inc.	-
Psoriasis	Preclinical	United States	Mylan Bertek Pharmaceuticals, Inc.	-

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AAIC2011	Not Applicable	Alzheimer Disease Aβ protein	32	Bapineuzumab 0.15 mg/kg	evietqznfz(wyejacyelt) = untrwhpgla xyxhnxajvp (pjginshqpz ) View more	-	01 Jul 2011
				Bapineuzumab 0.5 mg/kg	evietqznfz(wyejacyelt) = frpefppdxn xyxhnxajvp (pjginshqpz ) View more

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