5K0I

mpges1 bound to an inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.30 ?
  • R-Value Free: 0.159 
  • R-Value Work: 0.145 
  • R-Value Observed: 0.146 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Characterization of 3,3-dimethyl substituted N-aryl piperidines as potent microsomal prostaglandin E synthase-1 inhibitors.

Kuklish, S.L.Antonysamy, S.Bhattachar, S.N.Chandrasekhar, S.Fisher, M.J.Fretland, A.J.Gooding, K.Harvey, A.Hughes, N.E.Luz, J.G.Manninen, P.R.McGee, J.E.Navarro, A.Norman, B.H.Partridge, K.M.Quimby, S.J.Schiffler, M.A.Sloan, A.V.Warshawsky, A.M.York, J.S.Yu, X.P.

(2016) Bioorg Med Chem Lett 26: 4824-4828

  • DOI: https://doi.org/10.1016/j.bmcl.2016.08.023
  • Primary Citation of Related Structures:  
    5K0I

  • PubMed Abstract: 

    Here we report on novel, potent 3,3-dimethyl substituted N-aryl piperidine inhibitors of microsomal prostaglandin E synthases-1(mPGES-1). Example 14 potently inhibited PGE2 synthesis in an ex vivo human whole blood (HWB) assay with an IC50 of 7nM. In addition, 14 had no activity in human COX-1 or COX-2 assays at 30¦̀M, and failed to inhibit human mPGES-2 at 62.5¦̀M in a microsomal prep assay. These data are consistent with selective mPGES-1-mediated reduction of PGE2. In dog, 14 had oral bioavailability (74%), clearance (3.62mL/(min*kg)) and volume of distribution (Vd,ss=1.6L/kg) values within our target ranges. For these reasons, 14 was selected for further study.


  • Organizational Affiliation

    Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA. Electronic address: Kuklish_Steven@lilly.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Prostaglandin E synthase154Homo sapiensMutation(s): 0 
Gene Names: PTGESMGST1L1MPGES1PGESPIG12
EC: 5.3.99.3 (PDB Primary Data), 1.11.1 (UniProt), 2.5.1.18 (UniProt)
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for O14684 (Homo sapiens)
Explore O14684 
Go to UniProtKB:  O14684
PHAROS:  O14684
GTEx:  ENSG00000148344 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO14684
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6PW
Query on 6PW

Download Ideal Coordinates CCD File 
B [auth A]1,5-anhydro-2,3,4-trideoxy-3-{[(4S)-3,3-dimethyl-1-(8-methylquinolin-2-yl)piperidine-4-carbonyl]amino}-D-erythro-hexitol
C24 H33 N3 O3
OLJFTJILJDDJGV-SLFFLAALSA-N
GSH
Query on GSH

Download Ideal Coordinates CCD File 
C [auth A]GLUTATHIONE
C10 H17 N3 O6 S
RWSXRVCMGQZWBV-WDSKDSINSA-N
BOG
Query on BOG

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A]
octyl beta-D-glucopyranoside
C14 H28 O6
HEGSGKPQLMEBJL-RKQHYHRCSA-N
PG4
Query on PG4

Download Ideal Coordinates CCD File 
F [auth A],
G [auth A]
TETRAETHYLENE GLYCOL
C8 H18 O5
UWHCKJMYHZGTIT-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CSO
Query on CSO
A
L-PEPTIDE LINKINGC3 H7 N O3 SCYS
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.30 ?
  • R-Value Free: 0.159 
  • R-Value Work: 0.145 
  • R-Value Observed: 0.146 
  • Space Group: H 3
Unit Cell:
Length ( ? )Angle ( ? )
a = 77.444¦Á = 90
b = 77.444¦Â = 90
c = 123.565¦Ă = 120
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Department of Energy (DOE, United States)United StatesDE-AC02-06CH11357

Revision History  (Full details and data files)

  • Version 1.0: 2016-09-14
    Type: Initial release
  • Version 1.1: 2016-09-21
    Changes: Database references
  • Version 1.2: 2017-09-06
    Changes: Author supporting evidence, Database references, Derived calculations
  • Version 1.3: 2019-12-04
    Changes: Author supporting evidence
  • Version 1.4: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Derived calculations, Structure summary
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