5I7U

Human DPP4 in complex with a novel tricyclic hetero-cycle inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.187 
  • R-Value Work: 0.154 
  • R-Value Observed: 0.156 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Discovery of Novel Tricyclic Heterocycles as Potent and Selective DPP-4 Inhibitors for the Treatment of Type 2 Diabetes.

Wu, W.L.Hao, J.Domalski, M.Burnett, D.A.Pissarnitski, D.Zhao, Z.Stamford, A.Scapin, G.Gao, Y.D.Soriano, A.Kelly, T.M.Yao, Z.Powles, M.A.Chen, S.Mei, H.Hwa, J.

(2016) ACS Med Chem Lett 7: 498-501

  • DOI: https://doi.org/10.1021/acsmedchemlett.6b00027
  • Primary Citation of Related Structures:  
    5I7U

  • PubMed Abstract: 

    In our efforts to develop second generation DPP-4 inhibitors, we endeavored to identify distinct structures with long-acting (once weekly) potential. Taking advantage of X-ray cocrystal structures of sitagliptin and other DPP-4 inhibitors, such as alogliptin and linagliptin bound to DPP-4, and aided by molecular modeling, we designed several series of heterocyclic compounds as initial targets. During their synthesis, an unexpected chemical transformation provided a novel tricyclic scaffold that was beyond our original design. Capitalizing on this serendipitous discovery, we have elaborated this scaffold into a very potent and selective DPP-4 inhibitor lead series, as highlighted by compound 17c.


  • Organizational Affiliation

    Department of Lead Optimization Chemistry, Department of Structural Chemistry, Department of Pharmacology, and Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dipeptidyl peptidase 4
A, B
728Homo sapiensMutation(s): 1 
Gene Names: DPP4ADCP2CD26
EC: 3.4.14.5
UniProt & NIH Common Fund Data Resources
Find proteins for P27487 (Homo sapiens)
Explore P27487 
Go to UniProtKB:  P27487
PHAROS:  P27487
GTEx:  ENSG00000197635 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP27487
Sequence Annotations
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  • 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, D, E, F, G
C, D, E, F, G, H, I, J, K
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6AJ
Query on 6AJ

Download Ideal Coordinates CCD File 
M [auth A],
R [auth B]
2-({2-[(3R)-3-aminopiperidin-1-yl]-5-methyl-6,9-dioxo-5,6,7,9-tetrahydro-1H-imidazo[1,2-a]purin-1-yl}methyl)-4-fluorobenzonitrile
C21 H21 F N8 O2
KMOYVYIQCXEQDG-OAHLLOKOSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
L [auth A],
O [auth B],
P [auth B],
Q [auth B]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
N [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
6AJ BindingDB:  5I7U IC50: 1.7 (nM) from 1 assay(s)
Binding MOAD:  5I7U IC50: 1.7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.187 
  • R-Value Work: 0.154 
  • R-Value Observed: 0.156 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 118.553α = 90
b = 126.545β = 90
c = 137.854γ = 90
Software Package:
Software NamePurpose
BUSTER-TNTrefinement
SCALAdata scaling
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2016-06-08 
  • Deposition Author(s): Scapin, G.

Revision History  (Full details and data files)

  • Version 1.0: 2016-06-08
    Type: Initial release
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Data collection, Derived calculations, Structure summary
  • Version 2.1: 2023-09-27
    Changes: Data collection, Database references, Refinement description, Structure summary