3CCW

Thermodynamic and structure guided design of statin hmg-coa reductase inhibitors

3CCW の概要

• エントリーDOI: 10.2210/pdb3ccw/pdb
• 関連するPDBエントリー: 3CCT 3CCZ 3CD0 3CD5 3CD7 3CDA 3CDB
• 分子名称: 3-hydroxy-3-methylglutaryl-coenzyme A reductase, (3R,5R)-7-[4-(benzylcarbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl)-1H-imidazol-1-yl]-3,5-dihydroxyheptanoic acid (3 entities in total)
• 機能のキーワード: oxidoreductase, cholesterol biosynthesis, hmg-coa, nadph, statin, alternative splicing, endoplasmic reticulum, glycoprotein, lipid synthesis, membrane, peroxisome, polymorphism, steroid biosynthesis, transmembrane
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Endoplasmic reticulum membrane; Multi-pass membrane protein: P04035
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 191908.44

構造登録者

Pavlovsky, A.,Sarver, R.W.,Harris, M.S.,Finzel, B.C. (登録日: 2008-02-26, 公開日: 2008-06-17, 最終更新日: 2024-02-21)

主引用文献

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.
Thermodynamic and structure guided design of statin based inhibitors of 3-hydroxy-3-methylglutaryl coenzyme a reductase.
J.Med.Chem., 51:3804-3813, 2008

PubMed 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.

PubMed: 18540668
DOI: 10.1021/jm7015057

実験手法

X-RAY DIFFRACTION (2.1 Å)