3CD5: Thermodynamic And Structure Guided Design Of Statin Hmg-coa Reductase Inhibitors

Citation:
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.
PDB ID: 3CD5Download
MMDB ID: 64994
PDB Deposition Date: 2008/2/26
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 2.39  Å
Source Organism:
Similar Structures:
Biological Unit for 3CD5: tetrameric; determined by author and by software (PISA)
Molecular Components in 3CD5
Label Count Molecule
Proteins (4 molecules)
4
3-hydroxy-3-methylglutaryl-coenzyme a Reductase(Gene symbol: HMGCR)
Molecule annotation
Chemicals (8 molecules)
1
4
2
4
* Click molecule labels to explore molecular sequence information.

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