6ZBA

Crystal structure of PDE4D2 in complex with inhibitor LEO39652

PDB DOI: https://doi.org/10.2210/pdb6ZBA/pdb

Classification: HYDROLASE
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2020-06-08 Released: 2020-09-23
Deposition Author(s): Akutsu, M., Hakansson, M., Welin, M., Svensson, A., Logan, D.T., Sorensen, M.D.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.60 Å
R-Value Free: 0.192
R-Value Work: 0.162

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Discovery and Early Clinical Development of Isobutyl 1-[8-Methoxy-5-(1-oxo-3 H -isobenzofuran-5-yl)-[1,2,4]triazolo[1,5- a ]pyridin-2-yl]cyclopropanecarboxylate (LEO 39652), a Novel "Dual-Soft" PDE4 Inhibitor for Topical Treatment of Atopic Dermatitis.

Larsen, J., Lambert, M., Pettersson, H., Vifian, T., Larsen, M., Ollerstam, A., Hegardt, P., Eskilsson, C., Laursen, S., Soehoel, A., Skak-Nielsen, T., Hansen, L.M., Knudsen, N.O., Eirefelt, S., Sorensen, M.D., Stilou, T.G., Nielsen, S.F.

(2020) J Med Chem 63: 14502-14521

PubMed: 33054196 Search on PubMed
DOI: https://doi.org/10.1021/acs.jmedchem.0c00797
Primary Citation of Related Structures:
6ZBA

PubMed Abstract:
We describe the design of a novel PDE4 scaffold and the exploration of the dual-soft concept to reduce systemic side effects via rapid elimination: introducing ester functionalities that can be inactivated in blood as well as by the liver (dual-soft) while being stable in human skin. Compound 40 was selected as a clinical candidate as it was potent and rapidly degraded by blood and liver to inactive metabolites and because in preclinical studies it showed high exposure at the target organ: the skin. Preclinical and clinical data are presented confirming the value of the dual-soft concept in reducing systemic exposure.

Macromolecule Content

Total Structure Weight: 169.57 kDa
Atom Count: 12,640
Modelled Residue Count: 1,316
Deposited Residue Count: 1,440
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-specific 3',5'-cyclic phosphodiesterase 4D	A [auth AAA], B [auth BBB], C [auth CCC], D [auth DDD]	360	Homo sapiens	Mutation(s): 0 Gene Names: PDE4D, DPDE3 EC: 3.1.4.53
UniProt & NIH Common Fund Data Resources
Find proteins for Q08499 (Homo sapiens) Explore Q08499 Go to UniProtKB: Q08499
PHAROS: Q08499 GTEx: ENSG00000113448
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q08499
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
QDT (Subject of Investigation/LOI) Query on QDT Download Ideal Coordinates CCD File SDF format, chain AA [auth CCC] SDF format, chain E [auth AAA] SDF format, chain MA [auth DDD] SDF format, chain S [auth BBB] MOL2 format, chain AA [auth CCC] MOL2 format, chain E [auth AAA] MOL2 format, chain MA [auth DDD] MOL2 format, chain S [auth BBB] mmCIF format, chain AA [auth CCC] mmCIF format, chain E [auth AAA] mmCIF format, chain MA [auth DDD] mmCIF format, chain S [auth BBB]	AA [auth CCC], E [auth AAA], MA [auth DDD], S [auth BBB]	2-methylpropyl 1-[8-methoxy-5-(1-oxidanylidene-3~{H}-2-benzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropane-1-carboxylate C₂₃ H₂₃ N₃ O₅ LUUUHUYQTLUIDG-UHFFFAOYSA-N		Interactions Focus chain AA [auth CCC] Focus chain E [auth AAA] Focus chain MA [auth DDD] Focus chain S [auth BBB] Interactions & Density Focus chain AA [auth CCC] Focus chain E [auth AAA] Focus chain MA [auth DDD] Focus chain S [auth BBB]
DMS Query on DMS Download Ideal Coordinates CCD File SDF format, chain JA [auth CCC] SDF format, chain P [auth AAA] SDF format, chain TA [auth DDD] SDF format, chain X [auth BBB] MOL2 format, chain JA [auth CCC] MOL2 format, chain P [auth AAA] MOL2 format, chain TA [auth DDD] MOL2 format, chain X [auth BBB] mmCIF format, chain JA [auth CCC] mmCIF format, chain P [auth AAA] mmCIF format, chain TA [auth DDD] mmCIF format, chain X [auth BBB]	JA [auth CCC], P [auth AAA], TA [auth DDD], X [auth BBB]	DIMETHYL SULFOXIDE C₂ H₆ O S IAZDPXIOMUYVGZ-UHFFFAOYSA-N		Interactions Focus chain JA [auth CCC] Focus chain P [auth AAA] Focus chain TA [auth DDD] Focus chain X [auth BBB] Interactions & Density Focus chain JA [auth CCC] Focus chain P [auth AAA] Focus chain TA [auth DDD] Focus chain X [auth BBB]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain LA [auth CCC] SDF format, chain R [auth AAA] SDF format, chain VA [auth DDD] SDF format, chain Z [auth BBB] MOL2 format, chain LA [auth CCC] MOL2 format, chain R [auth AAA] MOL2 format, chain VA [auth DDD] MOL2 format, chain Z [auth BBB] mmCIF format, chain LA [auth CCC] mmCIF format, chain R [auth AAA] mmCIF format, chain VA [auth DDD] mmCIF format, chain Z [auth BBB]	LA [auth CCC], R [auth AAA], VA [auth DDD], Z [auth BBB]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain LA [auth CCC] Focus chain R [auth AAA] Focus chain VA [auth DDD] Focus chain Z [auth BBB] Interactions & Density Focus chain LA [auth CCC] Focus chain R [auth AAA] Focus chain VA [auth DDD] Focus chain Z [auth BBB]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain BA [auth CCC] SDF format, chain CA [auth CCC] SDF format, chain DA [auth CCC] SDF format, chain EA [auth CCC] SDF format, chain F [auth AAA] SDF format, chain FA [auth CCC] SDF format, chain G [auth AAA] SDF format, chain GA [auth CCC] SDF format, chain H [auth AAA] SDF format, chain HA [auth CCC] SDF format, chain I [auth AAA] SDF format, chain IA [auth CCC] SDF format, chain J [auth AAA] SDF format, chain K [auth AAA] SDF format, chain L [auth AAA] SDF format, chain M [auth AAA] SDF format, chain N [auth AAA] SDF format, chain NA [auth DDD] SDF format, chain O [auth AAA] SDF format, chain OA [auth DDD] SDF format, chain PA [auth DDD] SDF format, chain QA [auth DDD] SDF format, chain RA [auth DDD] SDF format, chain SA [auth DDD] SDF format, chain T [auth BBB] SDF format, chain U [auth BBB] SDF format, chain V [auth BBB] SDF format, chain W [auth BBB] MOL2 format, chain BA [auth CCC] MOL2 format, chain CA [auth CCC] MOL2 format, chain DA [auth CCC] MOL2 format, chain EA [auth CCC] MOL2 format, chain F [auth AAA] MOL2 format, chain FA [auth CCC] MOL2 format, chain G [auth AAA] MOL2 format, chain GA [auth CCC] MOL2 format, chain H [auth AAA] MOL2 format, chain HA [auth CCC] MOL2 format, chain I [auth AAA] MOL2 format, chain IA [auth CCC] MOL2 format, chain J [auth AAA] MOL2 format, chain K [auth AAA] MOL2 format, chain L [auth AAA] MOL2 format, chain M [auth AAA] MOL2 format, chain N [auth AAA] MOL2 format, chain NA [auth DDD] MOL2 format, chain O [auth AAA] MOL2 format, chain OA [auth DDD] MOL2 format, chain PA [auth DDD] MOL2 format, chain QA [auth DDD] MOL2 format, chain RA [auth DDD] MOL2 format, chain SA [auth DDD] MOL2 format, chain T [auth BBB] MOL2 format, chain U [auth BBB] MOL2 format, chain V [auth BBB] MOL2 format, chain W [auth BBB] mmCIF format, chain BA [auth CCC] mmCIF format, chain CA [auth CCC] mmCIF format, chain DA [auth CCC] mmCIF format, chain EA [auth CCC] mmCIF format, chain F [auth AAA] mmCIF format, chain FA [auth CCC] mmCIF format, chain G [auth AAA] mmCIF format, chain GA [auth CCC] mmCIF format, chain H [auth AAA] mmCIF format, chain HA [auth CCC] mmCIF format, chain I [auth AAA] mmCIF format, chain IA [auth CCC] mmCIF format, chain J [auth AAA] mmCIF format, chain K [auth AAA] mmCIF format, chain L [auth AAA] mmCIF format, chain M [auth AAA] mmCIF format, chain N [auth AAA] mmCIF format, chain NA [auth DDD] mmCIF format, chain O [auth AAA] mmCIF format, chain OA [auth DDD] mmCIF format, chain PA [auth DDD] mmCIF format, chain QA [auth DDD] mmCIF format, chain RA [auth DDD] mmCIF format, chain SA [auth DDD] mmCIF format, chain T [auth BBB] mmCIF format, chain U [auth BBB] mmCIF format, chain V [auth BBB] mmCIF format, chain W [auth BBB]	BA [auth CCC] CA [auth CCC] DA [auth CCC] EA [auth CCC] F [auth AAA] BA [auth CCC], CA [auth CCC], DA [auth CCC], EA [auth CCC], F [auth AAA], FA [auth CCC], G [auth AAA], GA [auth CCC], H [auth AAA], HA [auth CCC], I [auth AAA], IA [auth CCC], J [auth AAA], K [auth AAA], L [auth AAA], M [auth AAA], N [auth AAA], NA [auth DDD], O [auth AAA], OA [auth DDD], PA [auth DDD], QA [auth DDD], RA [auth DDD], SA [auth DDD], T [auth BBB], U [auth BBB], V [auth BBB], W [auth BBB]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain BA [auth CCC] Focus chain CA [auth CCC] Focus chain DA [auth CCC] Focus chain EA [auth CCC] Focus chain F [auth AAA] Focus chain FA [auth CCC] Focus chain G [auth AAA] Focus chain GA [auth CCC] Focus chain H [auth AAA] Focus chain HA [auth CCC] Focus chain I [auth AAA] Focus chain IA [auth CCC] Focus chain J [auth AAA] Focus chain K [auth AAA] Focus chain L [auth AAA] Focus chain M [auth AAA] Focus chain N [auth AAA] Focus chain NA [auth DDD] Focus chain O [auth AAA] Focus chain OA [auth DDD] Focus chain PA [auth DDD] Focus chain QA [auth DDD] Focus chain RA [auth DDD] Focus chain SA [auth DDD] Focus chain T [auth BBB] Focus chain U [auth BBB] Focus chain V [auth BBB] Focus chain W [auth BBB] Interactions & Density Focus chain BA [auth CCC] Focus chain CA [auth CCC] Focus chain DA [auth CCC] Focus chain EA [auth CCC] Focus chain F [auth AAA] Focus chain FA [auth CCC] Focus chain G [auth AAA] Focus chain GA [auth CCC] Focus chain H [auth AAA] Focus chain HA [auth CCC] Focus chain I [auth AAA] Focus chain IA [auth CCC] Focus chain J [auth AAA] Focus chain K [auth AAA] Focus chain L [auth AAA] Focus chain M [auth AAA] Focus chain N [auth AAA] Focus chain NA [auth DDD] Focus chain O [auth AAA] Focus chain OA [auth DDD] Focus chain PA [auth DDD] Focus chain QA [auth DDD] Focus chain RA [auth DDD] Focus chain SA [auth DDD] Focus chain T [auth BBB] Focus chain U [auth BBB] Focus chain V [auth BBB] Focus chain W [auth BBB]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain KA [auth CCC] SDF format, chain Q [auth AAA] SDF format, chain UA [auth DDD] SDF format, chain Y [auth BBB] MOL2 format, chain KA [auth CCC] MOL2 format, chain Q [auth AAA] MOL2 format, chain UA [auth DDD] MOL2 format, chain Y [auth BBB] mmCIF format, chain KA [auth CCC] mmCIF format, chain Q [auth AAA] mmCIF format, chain UA [auth DDD] mmCIF format, chain Y [auth BBB]	KA [auth CCC], Q [auth AAA], UA [auth DDD], Y [auth BBB]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain KA [auth CCC] Focus chain Q [auth AAA] Focus chain UA [auth DDD] Focus chain Y [auth BBB] Interactions & Density Focus chain KA [auth CCC] Focus chain Q [auth AAA] Focus chain UA [auth DDD] Focus chain Y [auth BBB]

Binding Affinity Annotations
ID	Source	Binding Affinity
QDT	BindingDB: 6ZBA	IC50: min: 1.2, max: 6 (nM) from 3 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.60 Å
R-Value Free: 0.192
R-Value Work: 0.162
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 100.03	α = 90
b = 111.866	β = 90
c = 159.623	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
XDS	data reduction
Aimless	data scaling
REFMAC	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2020-09-23

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2020-09-23
Type: Initial release
Version 1.1: 2020-10-28
Changes: Database references
Version 1.2: 2020-12-23
Changes: Database references
Version 1.3: 2024-01-24
Changes: Data collection, Database references, Derived calculations, Refinement description