1HY7

A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.190 

wwPDB Validation   3D Report Full Report


This is version 1.5 of the entry. See complete history


Literature

Development of new carboxylic acid-based MMP inhibitors derived from functionalized propargylglycines.

Natchus, M.G.Bookland, R.G.Laufersweiler, M.J.Pikul, S.Almstead, N.G.De, B.Janusz, M.J.Hsieh, L.C.Gu, F.Pokross, M.E.Patel, V.S.Garver, S.M.Peng, S.X.Branch, T.M.King, S.L.Baker, T.R.Foltz, D.J.Mieling, G.E.

(2001) J Med Chem 44: 1060-1071

  • DOI: https://doi.org/10.1021/jm000477l
  • Primary Citation of Related Structures:  
    1HY7

  • PubMed Abstract: 

    A series of carboxylic acids were prepared from a propargylglycine scaffold and tested for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for four enzymes within the MMP family. The inhibitors were typically potent against collagenase-3 (MMP-13) and gelatinase A (MMP-2), while they spared collagenase-1 (MMP-1) and only moderately inhibited stromelysin (MMP-3). Compound 40 represents a typical inhibition profile of a compound with reasonable potency. Introduction of polar groups was required in order to generate inhibitors with acceptable water solubility, and this often resulted in a loss of potency as in compound 63. High serum protein binding proved to be a difficult hurdle with many compounds such as 48 showing >99% binding. Some compounds such as 64 displayed approximately 90% binding, but no reliable method was discovered for designing molecules with low protein binding. Finally, selected data regarding the pharmacokinetic behavior of these compounds is presented.


  • Organizational Affiliation

    Procter and Gamble Pharmaceuticals, 8700 Mason-Montgomery Road, Mason, Ohio 45040, USA. natchus.mg@pg.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
STROMELYSIN-1
A, B
173Homo sapiensMutation(s): 0 
Gene Names: MMP3
EC: 3.4.24.17
UniProt & NIH Common Fund Data Resources
Find proteins for P08254 (Homo sapiens)
Explore P08254 
Go to UniProtKB:  P08254
PHAROS:  P08254
GTEx:  ENSG00000149968 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP08254
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
MBS
Query on MBS

Download Ideal Coordinates CCD File 
M [auth B]R-2-{[4'-METHOXY-(1,1'-BIPHENYL)-4-YL]-SULFONYL}-AMINO-6-METHOXY-HEX-4-YNOIC ACID
C20 H21 N O6 S
QJKGJGURDPRKGW-LJQANCHMSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
H [auth B],
I [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
G [auth A]
J [auth B]
K [auth B]
E [auth A],
F [auth A],
G [auth A],
J [auth B],
K [auth B],
L [auth B]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
MBS PDBBind:  1HY7 IC50: 4090 (nM) from 1 assay(s)
Binding MOAD:  1HY7 IC50: 4090 (nM) from 1 assay(s)
BindingDB:  1HY7 IC50: 4090 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.190 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 37.918α = 90
b = 78.059β = 90
c = 105.801γ = 90
Software Package:
Software NamePurpose
FFTmodel building
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling
FFTphasing
CCP4phasing

Structure Validation

View Full Validation Report



Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2002-01-18
    Type: Initial release
  • Version 1.1: 2008-04-27
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Derived calculations, Version format compliance
  • Version 1.3: 2017-10-04
    Changes: Refinement description
  • Version 1.4: 2018-02-07
    Changes: Experimental preparation
  • Version 1.5: 2024-02-07
    Changes: Data collection, Database references, Derived calculations