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Thermodynamic and Structure Guided Design of Statin Based Inhibitors of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase
Abstract
Clinical studies have demonstrated that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) inhibitors, are effective at lowering mortality levels associated with cardiovascular disease; however, 2-7% of patients may experience statin-induced myalgia that limits compliance with a treatment regimen. High resolution crystal structures, thermodynamic binding parameters, and biochemical data were used to design statin inhibitors with improved HMGR affinity and therapeutic index relative to statin-induced myalgia. These studies facilitated the identification of imidazole 1 as a potent (IC 50 = 7.9 nM) inhibitor with excellent hepatoselectivity (>1000-fold) and good in vivo efficacy. The binding of 1 to HMGR was found to be enthalpically driven with a Delta H of -17.7 kcal/M. Additionally, a second novel series of bicyclic pyrrole-based inhibitors was identified that induced order in a protein flap of HMGR. Similar ordering was detected in a substrate complex, but has not been reported in previous statin inhibitor complexes with HMGR.
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“An analysis of homology models for reductase of HMGCoA revealed 59.16% identity for coenzyme A reductase (HMG-CoA reductase) of 3-hydroxy-3-methylglutaryl (pdb: 3cd0) (Sarver et al. 2008).”
From In vitro study on the potential fungicidal effects of atorvastatin in combination with some azole drugs against multidrug resistant Candida albicans (2021) · cites this paper as Sarver et al. 2008
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Metadata
- Authors
- Sarver, R. W., Bills, E., Bolton, G., Bratton, L. D., Caspers, N. L., Dunbar, J. B., Harris, M. S., Hutchings, R. H., Kennedy, R. M., Larsen, S. D., Pavlovsky, A., Pfefferkorn, J. A., & Bainbridge, G.
- Affiliations
- Pfizer (United States) (US)
- Biogen (United States) (US)
- Corresponding author
- Sarver, Ronald W.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2008-07
- Volume
- 51
- Issue
- 13
- Pages
- 3804-3813
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W1978485989
- Cited by
- 65
- References
- 0
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 2 · 2023: 3 · 2022: 8 · 2021: 1 · 2020: 1 · 2019: 8 · 2018: 1 · 2017: 2 · 2016: 2 · 2015: 6 · 2014: 5 · 2013: 2 · 2012: 4
- FWCI
- 1.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Physical Sciences › Chemistry › Physical and Theoretical Chemistry › thermodynamics and calorimetric analyses
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Keywords
- statins, HMGR, statin-induced myalgia, binding thermodynamics, enthalpy-driven binding, substrate complex, therapeutic index, structure-based drug design
- MeSH terms
- Rosuvastatin Calcium, Animals, Binding Sites, Calorimetry, Cells, Cultured, Fluorobenzenes, Hydroxymethylglutaryl CoA Reductases, Imidazoles, Microsomes, Liver, Models, Molecular, Pyrimidines, Pyrroles, Structure-Activity Relationship, Sulfonamides, Thermodynamics, Drug Design, Molecular Structure, Crystallography, X-Ray, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hepatocytes, Muscle Cells, Mice, Rats
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