Cargando…

Virtual Screening of Novel 24-Dehydroxysterol Reductase (DHCR24) Inhibitors and the Biological Evaluation of Irbesartan in Cholesterol-Lowering Effect

Hyperlipidemia is a risk factor for the development of fatty liver and cardiovascular diseases such as atherosclerosis and coronary heart disease, and hence, cholesterol-lowering drugs are considered important and effective in preventing cardiovascular diseases. Thus, researchers in the field of new...

Descripción completa

Detalles Bibliográficos
Autores principales: Wang, Haozhen, Lu, Ziyin, Li, Yang, Liu, Ting, Zhao, Linlin, Gao, Tianqi, Lu, Xiuli, Gao, Bing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10053925/
https://www.ncbi.nlm.nih.gov/pubmed/36985615
http://dx.doi.org/10.3390/molecules28062643
_version_ 1785015529609625600
author Wang, Haozhen
Lu, Ziyin
Li, Yang
Liu, Ting
Zhao, Linlin
Gao, Tianqi
Lu, Xiuli
Gao, Bing
author_facet Wang, Haozhen
Lu, Ziyin
Li, Yang
Liu, Ting
Zhao, Linlin
Gao, Tianqi
Lu, Xiuli
Gao, Bing
author_sort Wang, Haozhen
collection PubMed
description Hyperlipidemia is a risk factor for the development of fatty liver and cardiovascular diseases such as atherosclerosis and coronary heart disease, and hence, cholesterol-lowering drugs are considered important and effective in preventing cardiovascular diseases. Thus, researchers in the field of new drug development are endeavoring to identify new types of cholesterol-lowering drugs. 3β-hydroxysterol-Δ(24)-reductase (DHCR24) catalyzes the conversion of desmosterol to cholesterol, which is the last step in the cholesterol biosynthesis pathway. We speculated that blocking the catalytic activity of DHCR24 could be a novel therapeutic strategy for treating hyperlipidemia. In the present study, by virtually screening the DrugBank database and performing molecular dynamics simulation analysis, we selected four potential DHCR24 inhibitor candidates: irbesartan, risperidone, tolvaptan, and conivaptan. All four candidates showed significant cholesterol-lowering activity in HepG2 cells. The experimental mouse model of hyperlipidemia demonstrated that all four candidates improved high blood lipid levels and fat vacuolation in the livers of mice fed with a high-fat diet. In addition, Western blot analysis results suggested that irbesartan reduced cholesterol levels by downregulating the expression of the low-density lipoprotein receptor. Finally, the immune complex activity assay confirmed the inhibitory effect of irbesartan on the enzymatic activity of DHCR24 with its half-maximal inhibitory concentration (IC50) value of 602 nM. Thus, to the best of our knowledge, this is the first study to report that blocking the enzymatic activity of DHCR24 via competitive inhibition is a potential strategy for developing new cholesterol-lowering drugs against hyperlipidemia or multiple cancers. Furthermore, considering that irbesartan is currently used to treat hypertension combined with type 2 diabetes, we believe that irbesartan should be a suitable choice for patients with both hypertension and hyperlipidemia.
format Online
Article
Text
id pubmed-10053925
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-100539252023-03-30 Virtual Screening of Novel 24-Dehydroxysterol Reductase (DHCR24) Inhibitors and the Biological Evaluation of Irbesartan in Cholesterol-Lowering Effect Wang, Haozhen Lu, Ziyin Li, Yang Liu, Ting Zhao, Linlin Gao, Tianqi Lu, Xiuli Gao, Bing Molecules Article Hyperlipidemia is a risk factor for the development of fatty liver and cardiovascular diseases such as atherosclerosis and coronary heart disease, and hence, cholesterol-lowering drugs are considered important and effective in preventing cardiovascular diseases. Thus, researchers in the field of new drug development are endeavoring to identify new types of cholesterol-lowering drugs. 3β-hydroxysterol-Δ(24)-reductase (DHCR24) catalyzes the conversion of desmosterol to cholesterol, which is the last step in the cholesterol biosynthesis pathway. We speculated that blocking the catalytic activity of DHCR24 could be a novel therapeutic strategy for treating hyperlipidemia. In the present study, by virtually screening the DrugBank database and performing molecular dynamics simulation analysis, we selected four potential DHCR24 inhibitor candidates: irbesartan, risperidone, tolvaptan, and conivaptan. All four candidates showed significant cholesterol-lowering activity in HepG2 cells. The experimental mouse model of hyperlipidemia demonstrated that all four candidates improved high blood lipid levels and fat vacuolation in the livers of mice fed with a high-fat diet. In addition, Western blot analysis results suggested that irbesartan reduced cholesterol levels by downregulating the expression of the low-density lipoprotein receptor. Finally, the immune complex activity assay confirmed the inhibitory effect of irbesartan on the enzymatic activity of DHCR24 with its half-maximal inhibitory concentration (IC50) value of 602 nM. Thus, to the best of our knowledge, this is the first study to report that blocking the enzymatic activity of DHCR24 via competitive inhibition is a potential strategy for developing new cholesterol-lowering drugs against hyperlipidemia or multiple cancers. Furthermore, considering that irbesartan is currently used to treat hypertension combined with type 2 diabetes, we believe that irbesartan should be a suitable choice for patients with both hypertension and hyperlipidemia. MDPI 2023-03-14 /pmc/articles/PMC10053925/ /pubmed/36985615 http://dx.doi.org/10.3390/molecules28062643 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Haozhen
Lu, Ziyin
Li, Yang
Liu, Ting
Zhao, Linlin
Gao, Tianqi
Lu, Xiuli
Gao, Bing
Virtual Screening of Novel 24-Dehydroxysterol Reductase (DHCR24) Inhibitors and the Biological Evaluation of Irbesartan in Cholesterol-Lowering Effect
title Virtual Screening of Novel 24-Dehydroxysterol Reductase (DHCR24) Inhibitors and the Biological Evaluation of Irbesartan in Cholesterol-Lowering Effect
title_full Virtual Screening of Novel 24-Dehydroxysterol Reductase (DHCR24) Inhibitors and the Biological Evaluation of Irbesartan in Cholesterol-Lowering Effect
title_fullStr Virtual Screening of Novel 24-Dehydroxysterol Reductase (DHCR24) Inhibitors and the Biological Evaluation of Irbesartan in Cholesterol-Lowering Effect
title_full_unstemmed Virtual Screening of Novel 24-Dehydroxysterol Reductase (DHCR24) Inhibitors and the Biological Evaluation of Irbesartan in Cholesterol-Lowering Effect
title_short Virtual Screening of Novel 24-Dehydroxysterol Reductase (DHCR24) Inhibitors and the Biological Evaluation of Irbesartan in Cholesterol-Lowering Effect
title_sort virtual screening of novel 24-dehydroxysterol reductase (dhcr24) inhibitors and the biological evaluation of irbesartan in cholesterol-lowering effect
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10053925/
https://www.ncbi.nlm.nih.gov/pubmed/36985615
http://dx.doi.org/10.3390/molecules28062643
work_keys_str_mv AT wanghaozhen virtualscreeningofnovel24dehydroxysterolreductasedhcr24inhibitorsandthebiologicalevaluationofirbesartanincholesterolloweringeffect
AT luziyin virtualscreeningofnovel24dehydroxysterolreductasedhcr24inhibitorsandthebiologicalevaluationofirbesartanincholesterolloweringeffect
AT liyang virtualscreeningofnovel24dehydroxysterolreductasedhcr24inhibitorsandthebiologicalevaluationofirbesartanincholesterolloweringeffect
AT liuting virtualscreeningofnovel24dehydroxysterolreductasedhcr24inhibitorsandthebiologicalevaluationofirbesartanincholesterolloweringeffect
AT zhaolinlin virtualscreeningofnovel24dehydroxysterolreductasedhcr24inhibitorsandthebiologicalevaluationofirbesartanincholesterolloweringeffect
AT gaotianqi virtualscreeningofnovel24dehydroxysterolreductasedhcr24inhibitorsandthebiologicalevaluationofirbesartanincholesterolloweringeffect
AT luxiuli virtualscreeningofnovel24dehydroxysterolreductasedhcr24inhibitorsandthebiologicalevaluationofirbesartanincholesterolloweringeffect
AT gaobing virtualscreeningofnovel24dehydroxysterolreductasedhcr24inhibitorsandthebiologicalevaluationofirbesartanincholesterolloweringeffect