3CDA

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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.07 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.214 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Thermodynamic and structure guided design of statin based inhibitors of 3-hydroxy-3-methylglutaryl coenzyme a reductase.

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.

(2008) J Med Chem 51: 3804-3813

  • DOI: https://doi.org/10.1021/jm7015057
  • Primary Citation of Related Structures:  
    3CCT, 3CCW, 3CCZ, 3CD0, 3CD5, 3CD7, 3CDA, 3CDB

  • 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.


  • Organizational Affiliation

    Pfizer Global Research & Development, Ann Arbor, Michigan 48105, USA. Ronald.w.sarver@pfizer.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
3-hydroxy-3-methylglutaryl-coenzyme A reductase
A, B, C, D
441Homo sapiensMutation(s): 1 
Gene Names: HMGCR
EC: 1.1.1.34
UniProt & NIH Common Fund Data Resources
Find proteins for P04035 (Homo sapiens)
Explore P04035 
Go to UniProtKB:  P04035
PHAROS:  P04035
GTEx:  ENSG00000113161 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04035
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
8HI Binding MOAD:  3CDA Kd: 26.3 (nM) from 1 assay(s)
PDBBind:  3CDA Kd: 26.3 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.07 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.214 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.611α = 90
b = 172.249β = 118.04
c = 75.62γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-06-17
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-10-25
    Changes: Refinement description
  • Version 1.3: 2021-10-20
    Changes: Database references, Derived calculations
  • Version 1.4: 2024-02-21
    Changes: Data collection