 |
PDBsum entry 3cdb
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Oxidoreductase
|
PDB id
|
|
|
|
3cdb
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Thermodynamic and structure guided design of statin based inhibitors of 3-Hydroxy-3-Methylglutaryl coenzyme a reductase.
|
|
|
Authors
|
|
R.W.Sarver,
E.Bills,
G.Bolton,
L.D.Bratton,
N.L.Caspers,
J.B.Dunbar,
M.S.Harris,
R.H.Hutchings,
R.M.Kennedy,
S.D.Larsen,
A.Pavlovsky,
J.A.Pfefferkorn,
G.Bainbridge.
|
|
|
Ref.
|
|
J Med Chem, 2008,
51,
3804-3813.
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
