Target Information

Target General Information

Target ID

T77613 (Former ID: TTDI02454)

Target Name

Phosphodiesterase 1B (PDE1B)

Synonyms

PDES1B; PDE1B1; CamPDE 1B; Cam-PDE 1B; Calcium/calmodulindependent 3',5'cyclicnucleotide phosphodiesterase 1B; Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B; 63 kDa CamPDE; 63 kDa Cam-PDE

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Gene Name

PDE1B

Target Type

Patented-recorded target

[1]

Disease

[+] 1 Target-related Diseases

Mild neurocognitive disorder [ICD-11: 6D71]

Function

Has a preference for cGMP as a substrate. Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.

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BioChemical Class

Phosphoric diester hydrolase

UniProt ID

PDE1B_HUMAN

EC Number

EC 3.1.4.17

Sequence

MELSPRSPPEMLEESDCPSPLELKSAPSKKMWIKLRSLLRYMVKQLENGEINIEELKKNL
EYTASLLEAVYIDETRQILDTEDELQELRSDAVPSEVRDWLASTFTQQARAKGRRAEEKP
KFRSIVHAVQAGIFVERMFRRTYTSVGPTYSTAVLNCLKNLDLWCFDVFSLNQAADDHAL
RTIVFELLTRHNLISRFKIPTVFLMSFLDALETGYGKYKNPYHNQIHAADVTQTVHCFLL
RTGMVHCLSEIELLAIIFAAAIHDYEHTGTTNSFHIQTKSECAIVYNDRSVLENHHISSV
FRLMQDDEMNIFINLTKDEFVELRALVIEMVLATDMSCHFQQVKTMKTALQQLERIDKPK
ALSLLLHAADISHPTKQWLVHSRWTKALMEEFFRQGDKEAELGLPFSPLCDRTSTLVAQS
QIGFIDFIVEPTFSVLTDVAEKSVQPLADEDSKSKNQPSFQWRQPSLDVEVGDPNPDVVS
FRSTWVKRIQENKQKWKERAASGITNQMSIDELSPCEEEAPPSPAEDEHNQNGNLD

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3D Structure

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AlphaFold

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: ITI-214

Ligand Info

Structure Description

Crystal structure of human PDE1B with inhibitor 3

PDB:5B25

Method

X-ray diffraction

Resolution

1.90 Å

Mutation

[7]

PDB Sequence

TYSTAVLNCL

¹⁵⁸

KNLDLWCFDV

¹⁶⁸

FSLNQAADDH

¹⁷⁸

ALRTIVFELL

¹⁸⁸

TRHNLISRFK

¹⁹⁸

IPTVFLMSFL

²⁰⁸

DALETGYGKY

²¹⁸

KNPYHNQIHA

²²⁸

ADVTQTVHCF

²³⁸

LLRTGMVHCL

²⁴⁸

SEIELLAIIF

²⁵⁸

AAAIHDYEHT

²⁶⁸

GTTNSFHIQT

²⁷⁸

KSECAIVYND

²⁸⁸

RSVLENHHIS

²⁹⁸

SVFRLMQDDE

³⁰⁸

MNIFINLTKD

³¹⁸

EFVELRALVI

³²⁸

EMVLATDMSC

³³⁸

HFQQVKTMKT

³⁴⁸

ALQQLERIDK

³⁵⁸

PKALSLLLHA

³⁶⁸

ADISHPTKQW

³⁷⁸

LVHSRWTKAL

³⁸⁸

MEEFFRQGDK

³⁹⁸

EAELGLPFSP

⁴⁰⁸

LCDRTSTLVA

⁴¹⁸

QSQIGFIDFI

⁴²⁸

VEPTFSVLTD

⁴³⁸

VAEKSVQPLA

⁴⁴⁸

GDPNPDVVSF

⁴⁸¹

RSTWVKRIQE

⁴⁹¹

NKQKWKERAA

⁵⁰¹

SGITN

Residue

Distance (Å)

TYR222

3.719

HIS223

3.916

MET336

3.905

PHE340

3.922

ASP370

4.232

ILE371

3.547

HIS373

3.293

PRO374

4.624

THR385

4.411

LEU388

3.345

MET389

4.224

Residue

Distance (Å)

PHE392

3.685

LEU409

3.421

THR415

4.982

VAL417

3.588

SER420

3.620

GLN421

2.809

GLY423

3.611

PHE424

3.363

PHE427

3.570

ILE428

4.042

Ligand Name: 7,8-Dimethoxy-N-[(2s)-1-(3-Methyl-1h-Pyrazol-5-Yl)propan-2-Yl]quinazolin-4-Amine

Ligand Info

Structure Description

Crystal structure of human PDE1B bound to inhibitor 19A (7,8-dimethoxy-N-[(2S)-1-(3-methyl-1H-pyrazol-5-yl)propan-2-yl]quinazolin-4-amine)

PDB:4NPW

Method

X-ray diffraction

Resolution

1.90 Å

Mutation

[8]

PDB Sequence

YSTAVLNCLK

¹⁵⁹

NLDLWCFDVF

¹⁶⁹

SLNQAADDHA

¹⁷⁹

LRTIVFELLT

¹⁸⁹

RHNLISRFKI

¹⁹⁹

PTVFLMSFLD

²⁰⁹

ALETGYGKYK

²¹⁹

NPYHNQIHAA

²²⁹

DVTQTVHCFL

²³⁹

LRTGMVHCLS

²⁴⁹

EIELLAIIFA

²⁵⁹

AAIHDYEHTG

²⁶⁹

TTNSFHIQTK

²⁷⁹

SECAIVYNDR

²⁸⁹

SVLENHHISS

²⁹⁹

VFRLMQDDEM

³⁰⁹

NIFINLTKDE

³¹⁹

FVELRALVIE

³²⁹

MVLATDMSCH

³³⁹

FQQVKTMKTA

³⁴⁹

LQQLERIDKP

³⁵⁹

KALSLLLHAA

³⁶⁹

DISHPTKQWL

³⁷⁹

VHSRWTKALM

³⁸⁹

EEFFRQGDKE

³⁹⁹

AELGLPFSPL

⁴⁰⁹

CDRTSTLVAQ

⁴¹⁹

SQIGFIDFIV

⁴²⁹

EPTFSVLTDV

⁴³⁹

AEKSVQVVSF

⁴⁸¹

RSTWVKRIQE

⁴⁹¹

NKQKWKERAA

⁵⁰¹

Residue

Distance (Å)

TYR222

3.381

HIS223

3.349

HIS267

4.657

THR271

3.935

THR334

4.965

MET336

3.851

ASP370

4.037

ILE371

3.991

HIS373

2.818

PRO374

3.799

Residue

Distance (Å)

LEU388

3.304

MET389

4.131

GLU391

3.739

PHE392

3.582

LEU409

3.619

SER420

3.847

GLN421

2.919

PHE424

3.414

VAL429

4.835

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Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

There is no similarity protein (E value < 0.005) for this target


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target
Purine metabolism	hsa00230	Affiliated Target
Class: Metabolism => Nucleotide metabolism	Pathway Hierarchy
Calcium signaling pathway	hsa04020	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Olfactory transduction	hsa04740	Affiliated Target
Class: Organismal Systems => Sensory system	Pathway Hierarchy
Taste transduction	hsa04742	Affiliated Target
Class: Organismal Systems => Sensory system	Pathway Hierarchy
Renin secretion	hsa04924	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 3 KEGG Pathways

Purine metabolism

Calcium signaling pathway

Morphine addiction

Reactome

[+] 2 Reactome Pathways

cGMP effects

G alpha (s) signalling events

WikiPathways

[+] 3 WikiPathways

G Protein Signaling Pathways

DAG and IP3 signaling

Opioid Signalling

References

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REF 1

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1295).

REF 2

Substituted thiophene- and furan-fused azolopyrimidine-5-(6H)-one compounds. US10092575.

REF 3

Inhibitors of phosphodiesterase 11 (PDE11). US9173884.

REF 4

1H-pyrazolo[4,3-b]pyridines as PDE1 inhibitors. US10034861.

REF 5

Organic compounds. US9598426.

REF 6

Antiplatelet and antiproliferative effects of SCH 51866, a novel type 1 and type 5 phosphodiesterase inhibitor. J Cardiovasc Pharmacol. 1996 Dec;28(6):862-9.

REF 7

Discovery of Potent and Selective Inhibitors of Phosphodiesterase 1 for the Treatment of Cognitive Impairment Associated with Neurodegenerative and Neuropsychiatric Diseases. J Med Chem. 2016 Feb 11;59(3):1149-64.

REF 8

Small-molecule phosphodiesterase probes: discovery of potent and selective CNS-penetrable quinazoline inhibitors of PDE1. doi:10.1039/C4MD00113C.

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