5SY3

Structure-based design of a new series of N-piperidin-3-ylpyrimidine-5-carboxamides as renin inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.194 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.0 of the entry. See complete history


Literature

Structure-based design of a new series of N-(piperidin-3-yl)pyrimidine-5-carboxamides as renin inhibitors.

Imaeda, Y.Tawada, M.Suzuki, S.Tomimoto, M.Kondo, M.Tarui, N.Sanada, T.Kanagawa, R.Snell, G.Behnke, C.A.Kubo, K.Kuroita, T.

(2016) Bioorg Med Chem 24: 5771-5780

  • DOI: https://doi.org/10.1016/j.bmc.2016.09.030
  • Primary Citation of Related Structures:  
    5KOQ, 5SXN, 5SY2, 5SY3, 5SZ9

  • PubMed Abstract: 

    The action of the aspartyl protease renin is the rate-limiting initial step of the renin-angiotensin-aldosterone system. Therefore, renin is a particularly promising target for blood pressure as well as onset and progression of cardiovascular and renal diseases. New pyrimidine derivatives 5-14 were designed in an attempt to enhance the renin inhibitory activity of compound 3 identified by our previous fragment-based drug design approach. Introduction of a basic amine essential for interaction with the two aspartic acids in the catalytic site and optimization of the S1/S3 binding elements including an induced-fit structural change of Leu114 ('Leu-in' to 'Leu-out') by a rational structure-based drug design approach led to the discovery of N-(piperidin-3-yl)pyrimidine-5-carboxamide 14, a 65,000-fold more potent renin inhibitor than compound 3. Surprisingly, this remarkable enhancement in the inhibitory activity of compound 14 has been achieved by the overall addition of only seven heavy atoms to compound 3. Compound 14 demonstrated excellent selectivity over other aspartyl proteases and moderate oral bioavailability in rats.


  • Organizational Affiliation

    Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: yasuhiro.imaeda@takeda.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Renin
A, B
339Homo sapiensMutation(s): 0 
Gene Names: REN
EC: 3.4.23.15
UniProt & NIH Common Fund Data Resources
Find proteins for P00797 (Homo sapiens)
Explore P00797 
Go to UniProtKB:  P00797
PHAROS:  P00797
GTEx:  ENSG00000143839 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00797
Sequence Annotations
Expand
  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
C
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
74Z
Query on 74Z

Download Ideal Coordinates CCD File 
E [auth A]N-[(furan-2-yl)methyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine
C15 H15 N3 O S
OZBAWCPXMIEVSW-UHFFFAOYSA-N
1PE
Query on 1PE

Download Ideal Coordinates CCD File 
L [auth A],
N [auth B]
PENTAETHYLENE GLYCOL
C10 H22 O6
JLFNLZLINWHATN-UHFFFAOYSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
D [auth A]2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
PEG
Query on PEG

Download Ideal Coordinates CCD File 
K [auth A],
O [auth B]
DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
F [auth A]
G [auth A]
H [auth A]
I [auth A]
J [auth A]
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
M [auth A],
P [auth B],
Q [auth B],
R [auth B],
S [auth B],
T [auth B],
U [auth B]
DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
74Z Binding MOAD:  5SY3 IC50: 4.30e+4 (nM) from 1 assay(s)
BindingDB:  5SY3 IC50: 4.30e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.194 
  • Space Group: P 21 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 139.192α = 90
b = 139.192β = 90
c = 139.192γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
HKL-2000data scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-11-02
    Type: Initial release
  • Version 1.1: 2016-11-09
    Changes: Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Database references, Derived calculations, Structure summary