2Y0J

Triazoloquinazolines as a novel class of phosphodiesterase 10A (PDE10A) inhibitors, part 2, Lead-optimisation.

PDB DOI: https://doi.org/10.2210/pdb2Y0J/pdb

Classification: HYDROLASE
Organism(s): Homo sapiens
Expression System: Spodoptera frugiperda
Mutation(s): No

Deposited: 2010-12-03 Released: 2011-06-15
Deposition Author(s): Kehler, J., Ritzen, A., Langgard, M., Petersen, S.L., Christoffersen, C.T., Nielsen, J., Kilburn, J.P.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.43 Å
R-Value Free: 0.284
R-Value Work: 0.221
R-Value Observed: 0.224

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Triazoloquinazolines as a Novel Class of Phosphodiesterase 10A (Pde10A) Inhibitors.

Kehler, J., Ritzen, A., Langgard, M., Petersen, S.L., Farah, M.M., Bundgaard, C., Christoffersen, C.T., Nielsen, J., Kilburn, J.P.

(2011) Bioorg Med Chem Lett 21: 3738

PubMed: 21602043 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2011.04.067
Primary Citation of Related Structures:
2Y0J

PubMed Abstract:
Novel triazoloquinazolines have been found as phosphodiesterase 10A (PDE10A) inhibitors. Structure-activity studies improved the initial micromolar potency which was found in the lead compound by a 100-fold identifying 5-(1H-benzoimidazol-2-ylmethylsulfanyl)-2-methyl-[1,2,4]triazolo[1,5-c]quinazoline, 42 (PDE10A IC(50)=12 nM) as the most potent compound from the series. Two X-ray structures revealed novel binding modes to the catalytic site of the PDE10A enzyme.

Organizational Affiliation

H. Lundbeck A/S, Department of Discovery Chemistry & DMPK, Valby, Denmark. jke@lundbeck.com

Macromolecule Content

Total Structure Weight: 80.13 kDa
Atom Count: 5,315
Modelled Residue Count: 628
Deposited Residue Count: 680
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
CAMP AND CAMP-INHIBITED CGMP 3', 5'-CYCLIC PHOSPHODIESTERASE 10A	A, B	340	Homo sapiens	Mutation(s): 0 EC: 3.1.4.17
UniProt & NIH Common Fund Data Resources
Find proteins for Q9Y233 (Homo sapiens) Explore Q9Y233 Go to UniProtKB: Q9Y233
PHAROS: Q9Y233 GTEx: ENSG00000112541
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q9Y233
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
AXC Query on AXC Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain F [auth B] MOL2 format, chain C [auth A] MOL2 format, chain F [auth B]	C [auth A], F [auth B]	5-(1H-BENZIMIDAZOL-2-YLMETHYLSULFANYL)-2-METHYL-[1,2,4]TRIAZOLO[1,5-C]QUINAZOLINE C₁₈ H₁₄ N₆ S VVYNKZKNFFKZDW-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain F [auth B] Interactions & Density Focus chain C [auth A] Focus chain F [auth B]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain G [auth B] MOL2 format, chain D [auth A] MOL2 format, chain G [auth B]	D [auth A], G [auth B]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain G [auth B] Interactions & Density Focus chain D [auth A] Focus chain G [auth B]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain H [auth B] MOL2 format, chain E [auth A] MOL2 format, chain H [auth B]	E [auth A], H [auth B]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain H [auth B] Interactions & Density Focus chain E [auth A] Focus chain H [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
AXC	PDBBind: 2Y0J	IC50: 12 (nM) from 1 assay(s)
	BindingDB: 2Y0J	IC50: 12 (nM) from 1 assay(s)
	Binding MOAD: 2Y0J	IC50: 12 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.43 Å
R-Value Free: 0.284
R-Value Work: 0.221
R-Value Observed: 0.224
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 49.38	α = 90
b = 81.69	β = 90
c = 160.62	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
MOSFLM	data reduction
SCALA	data scaling
MOLREP	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2011-06-15

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2011-06-15
Type: Initial release
Version 1.1: 2011-07-13
Changes: Version format compliance
Version 1.2: 2023-12-20
Changes: Data collection, Database references, Derived calculations, Other, Refinement description