3QPP

Structure of PDE10-inhibitor complex

PDB DOI: https://doi.org/10.2210/pdb3QPP/pdb

Classification: HYDROLASE/HYDROLASE INHIBITOR
Organism(s): Rattus norvegicus
Expression System: Spodoptera frugiperda
Mutation(s): No

Deposited: 2011-02-14 Released: 2011-06-15
Deposition Author(s): Pandit, J., Marr, E.S.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.80 Å
R-Value Free: 0.210
R-Value Work: 0.184
R-Value Observed: 0.186

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Use of Structure-Based Design to Discover a Potent, Selective, In Vivo Active Phosphodiesterase 10A Inhibitor Lead Series for the Treatment of Schizophrenia.

Helal, C.J., Kang, Z., Hou, X., Pandit, J., Chappie, T.A., Humphrey, J.M., Marr, E.S., Fennell, K.F., Chenard, L.K., Fox, C., Schmidt, C.J., Williams, R.D., Chapin, D.S., Siuciak, J., Lebel, L., Menniti, F., Cianfrogna, J., Fonseca, K.R., Nelson, F.R., O'Connor, R., Macdougall, M., McDowell, L., Liras, S.

(2011) J Med Chem 54: 4536-4547

PubMed: 21650160 Search on PubMed
DOI: https://doi.org/10.1021/jm2001508
Primary Citation of Related Structures:
3QPN, 3QPO, 3QPP

PubMed Abstract:
Utilizing structure-based virtual library design and scoring, a novel chimeric series of phosphodiesterase 10A (PDE10A) inhibitors was discovered by synergizing binding site interactions and ADME properties of two chemotypes. Virtual libraries were docked and scored for potential binding ability, followed by visual inspection to prioritize analogs for parallel and directed synthesis. The process yielded highly potent and selective compounds such as 16. New X-ray cocrystal structures enabled rational design of substituents that resulted in the successful optimization of physical properties to produce in vivo activity and to modulate microsomal clearance and permeability.

Organizational Affiliation

Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States. chris.j.helal@pfizer.com

Macromolecule Content

Total Structure Weight: 42.49 kDa
Atom Count: 2,817
Modelled Residue Count: 305
Deposited Residue Count: 362
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(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	362	Rattus norvegicus	Mutation(s): 0 Gene Names: Pde10a EC: 3.1.4.17 (PDB Primary Data), 3.1.4.35 (PDB Primary Data)
UniProt
Find proteins for Q9QYJ6 (Rattus norvegicus) Explore Q9QYJ6 Go to UniProtKB: Q9QYJ6
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q9QYJ6
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
PFW Query on PFW Download Ideal Coordinates CCD File SDF format, chain G [auth A] MOL2 format, chain G [auth A]	G [auth A]	7-methoxy-4-[(3S)-3-phenylpiperidin-1-yl]-6-[2-(quinolin-2-yl)ethoxy]quinazoline C₃₁ H₃₀ N₄ O₂ MUQUFIBWWXZLNL-XMMPIXPASA-N		Interactions Focus chain G [auth A] Interactions & Density Focus chain G [auth A]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain D [auth A] MOL2 format, chain D [auth A]	D [auth A]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]
DMS Query on DMS Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A]	E [auth A], F [auth A]	DIMETHYL SULFOXIDE C₂ H₆ O S IAZDPXIOMUYVGZ-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain F [auth A] Interactions & Density Focus chain E [auth A] Focus chain F [auth A]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A]	B [auth A]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A]	C [auth A]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
PFW	PDBBind: 3QPP	IC50: 12 (nM) from 1 assay(s)
	Binding MOAD: 3QPP	IC50: 12 (nM) from 1 assay(s)
	BindingDB: 3QPP	IC50: 12 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.80 Å
R-Value Free: 0.210
R-Value Work: 0.184
R-Value Observed: 0.186
Space Group: H 3

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 120.616	α = 90
b = 120.616	β = 90
c = 84.008	γ = 120

Software Package:

Software Name	Purpose
d*TREK	data scaling
REFMAC	refinement
PDB_EXTRACT	data extraction

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2011-06-15

Deposition Author(s):

Pandit, J.

Marr, E.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: 2011-07-20
Changes: Database references
Version 1.3: 2024-02-21
Changes: Data collection, Database references, Derived calculations