Phosphodiesterases (PDE) are a family of enzymes that degrade the phosphodiester bond in the second messenger molecules, cAMP and cGMP, to terminate signal transduction [1]. It is an attractive drug target for drug discovery projects aimed at findingeffective and selective treatment of degenerative CNS disorders.
A unique method for in silico search of potential phosphodiesterase PDE10 inhibitors has been developed by our cheminformatics team by combining different computational approaches. This work involved our in-house HTS Compound Collection and led to the selection of 2,800 small-molecule screening compounds organized into two dedicated Screening Sets:
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Background information
Dual cAMP/cGMP phosphodiesterase is expressed at high levels in the striatal medium spiny neurons [2]. While elsewhere in the brain and other tissues the level of its expression is very low. It was found that inhibitors of phosphodiesterase, for example PDE10, may potentially cure psychiatric and neurological diseases, including schizophrenia, delusional disorder, anxiety disorders, Alzheimer’s disease, movement disorders such as Parkinson’s and Huntington’s diseases [3]. However, cognitive dysfunction, responsible for substantial disability in most of these diseases, is not improved significantly by current medications [4].
Phosphodiesterase Focused Set
This ligand-based Screening Library was prepared through a 2D fingerprint similarity search against the Life Chemicals HTS Compound Collection. First, a reference set (209K molecules) based on the published data on compounds with proven phosphodiesterase bioactivities from the ChEMBL database was prepared. After this, the application of the minimum Tanimoto index > 0.80 allowed us to identify over 3,000 structural analogs of reported phosphodiesterase modulators. The resulting screening compound selection was reduced by structural dissimilarity to provide 1,400 drug-like small molecules with predicted activity against the following phosphodiesterase drug targets:
- cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
- Ectonucleotide pyrophosphatase/phosphodiesterase family member 2
- Ectonucleotide pyrophosphatase/phosphodiesterase family member 7
- Neutral sphingomyelinase
- Phosphodiesterase 10A
- Phosphodiesterase 1C
- Phosphodiesterase 2A
- Phosphodiesterase 3A
- Phosphodiesterase 4A
- Phosphodiesterase 4B
- Phosphodiesterase 4D
- Phosphodiesterase 5A
- Phosphodiesterase 7A
- Phosphodiesterase 8A
- Phosphodiesterase 8B
- Phosphodiesterase 9A
- Sphingomyelin phosphodiesterase
- Tyrosyl-DNA phosphodiesterase 1
- Tyrosyl-DNA phosphodiesterase 2
Figure 1. Target distribution in the Phosphodiesterase-focused Screening Set
Representative screening compounds from the Phosphodiesterase-focused Screening Set
Phosphodiesterase Targeted Set
This target-based Screening Library was prepared through structure-based virtual screening. At the first stage, all available X-ray structures of PDE10 complexed with a small-molecule phosphodiesterase inhibitor were obtained from the Protein Data Bank (data based on fragment-like molecules were excluded). Then, diversity analysis and discarding the most similar structures resulted in generation of 42 3D pharmacophore models (Fig. 1), subsequently screened against the Life Chemicals HTS Compound Collection. In addition to ligand features, the models included PDE10A active site boundaries.
About 10,000 virtual screening hit compounds were revealed with the help of 12 pharmacophore hypotheses and then passed to the second stage - molecular docking. The docking (Glide, Schrödinger) was performed on the basis of 3 conformationally different PDE10A structures. After the docking and manual inspection of the complexes, 1,400 best-scored and structurally-diverse potential phosphodiesterase PDE10 inhibitors were selected (Fig. 2). The library is Ro5-compliant and does not contain PAINS, toxic and reactive compounds.
Key features:
- Method: structure-based virtual screening using Phase (receptor-ligand complex)
- X-Ray data used: 3WI2
- Filters used: no
- Number of compounds selected: 1,451
Figure 1. Compound F1300-0246 (green) in the binding site of PDE10A with inhibitor (pink) complex (PDB ID: 3WI2).
Figure 2. Examples of the virtual hit molecules obtained after docking.
References:
- Menniti, Frank S et al. “Phosphodiesterases in the CNS: targets for drug development.” Nature reviews. Drug discovery vol. 5,8 (2006): 660-70. doi:10.1038/nrd2058
- Menniti, Frank S et al. “PDE10A Inhibitors-Clinical Failure or Window Into Antipsychotic Drug Action?.” Frontiers in neuroscience vol. 14 600178. 20 Jan. 2021, doi:10.3389/fnins.2020.600178
- Menniti FS, Chappie TA, Humphrey JM, Schmidt CJ. Phosphodiesterase 10A inhibitors: a novel approach to the treatment of the symptoms of schizophrenia. Curr Opin Investig Drugs. 2007, 8(1):54-9.
- Aarsland, Dag et al. “Cognitive decline in Parkinson disease.” Nature reviews. Neurology vol. 13,4 (2017): 217-231. doi:10.1038/nrneurol.2017.27