Predictive Modeling of HMG-CoA Reductase Inhibitory Activity and Design of New HMG-CoA Reductase Inhibitors.
Journal
ACS omega
ISSN: 2470-1343
Titre abrégé: ACS Omega
Pays: United States
ID NLM: 101691658
Informations de publication
Date de publication:
01 Aug 2023
01 Aug 2023
Historique:
received:
14
04
2023
accepted:
30
06
2023
medline:
7
8
2023
pubmed:
7
8
2023
entrez:
7
8
2023
Statut:
epublish
Résumé
As blood cholesterol increases, it accumulates in the intima of blood vessels, elevating the risk of atherosclerosis and coronary artery disease. Drugs that inhibit enzymes essential for cholesterol synthesis are effective in improving blood cholesterol levels. Statins are used to treat hypercholesterolemia as they inhibit 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR), the rate-limiting enzyme in cholesterol synthesis. Statins are known to exert their effects by translocating to the liver, where they are taken up by the organic anion transporting polypeptide 1B1 (OATP1B1). Therefore, we hypothesized that a compound with high HMGR inhibitory activity and high affinity for OATP1B1 would be an excellent new therapeutic agent for hypercholesterolemia with increased liver selectivity and fewer side effects. In this study, we developed two models for predicting HMGR inhibitory activity and OATP1B1 affinity to propose the chemical structure of a new therapeutic agent for hypercholesterolemia with both high inhibitory activity and high liver selectivity. HMGR inhibitory activity and OATP1B1 affinity prediction models were constructed with high prediction accuracy for the test data:
Identifiants
pubmed: 37546661
doi: 10.1021/acsomega.3c02567
pmc: PMC10399166
doi:
Types de publication
Journal Article
Langues
eng
Pagination
27247-27255Informations de copyright
© 2023 The Authors. Published by American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare no competing financial interest.
Références
Drug Des Devel Ther. 2015 Jan 22;9:643-53
pubmed: 25653502
J Chem Inf Model. 2020 Dec 28;60(12):6065-6073
pubmed: 33118813
PLoS One. 2013 Dec 30;8(12):e83496
pubmed: 24386216
Biochim Biophys Acta. 2004 Jul 1;1664(1):64-9
pubmed: 15238259
J Comb Chem. 2007 Jan-Feb;9(1):131-8
pubmed: 17206841
Xenobiotica. 2016;46(5):457-66
pubmed: 26383540
Org Med Chem Lett. 2012 Jul 02;2(1):25
pubmed: 22747771
Int J Oncol. 2015 Jan;46(1):324-32
pubmed: 25351763
Mol Inform. 2021 Mar;40(3):e2000123
pubmed: 32893463
Drug Metab Dispos. 2013 Mar;41(3):592-601
pubmed: 23248200
J Pharm Sci. 2017 Sep;106(9):2515-2523
pubmed: 28535976
JAMA. 1986 Nov 28;256(20):2849-58
pubmed: 3534335
Gastroenterology. 2006 May;130(6):1793-806
pubmed: 16697742
Phytother Res. 2019 Jan;33(1):197-204
pubmed: 30402894
J Med Chem. 1990 Jan;33(1):52-60
pubmed: 2296036
J Chem Inf Model. 2009 Jul;49(7):1762-76
pubmed: 19530661
Bioorg Med Chem Lett. 2014 Aug 15;24(16):3869-76
pubmed: 25022881
J Comput Aided Mol Des. 2000 Oct;14(7):647-57
pubmed: 11008886
Mol Pharm. 2016 Feb 1;13(2):438-48
pubmed: 26696140
Pharmacol Res. 2009 Jul;60(1):50-6
pubmed: 19427586
Nat Rev Drug Discov. 2003 Mar;2(3):192-204
pubmed: 12612645
Mol Inform. 2010 Jul 12;29(6-7):476-88
pubmed: 27463326
PLoS One. 2017 Jan 6;12(1):e0169719
pubmed: 28060902
Nature. 2002 Nov 14;420(6912):206-10
pubmed: 12432404
Genome Biol. 2004;5(11):248
pubmed: 15535874
Science. 2001 May 11;292(5519):1160-4
pubmed: 11349148
Drug Metab Dispos. 2014 Jul;42(7):1210-8
pubmed: 24799396
J Med Chem. 2008 May 8;51(9):2722-33
pubmed: 18412317
Cardiovasc Drugs Ther. 2003 Sep-Nov;17(5-6):459-65
pubmed: 15107601