Caspase Focused and Targeted Libraries | Protease Screening Libraries | Targeted and Focused Screening Libraries

Caspases are a family of cysteine proteases known to provide critically important links in cell regulatory systems controlling inflammation and apoptosis (programmed cell death). Needless to say, the latter is vital to maintaining the body’s health by eliminating old, unnecessary, or unhealthy cells [1-2]. Dysregulation of caspases underlies various human diseases, including cancer and mentioned above inflammatory disorders, and, thus, serious efforts must be aimed at understanding the mechanism of their work and regulation to design better therapies for these alarming medical conditions

Being at the forefront of medicinal chemistry R&D, Life Chemicals has designed its Caspase Targeted and Focused Libraries of over 24,400 structurally diverse screening compounds to identify potential caspase inhibitors using several cheminformatics approaches:

This Caspase Screening Library can be used for cell survival, proliferation, apoptosis, inflammation, and epidermal formation research in drug discovery projects dedicated to the solution of many pressing medical problems.

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.

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Background information

Increased levels of cellular apoptosis and caspase activity are frequently observed at sites of cellular damage in both acute (myocardial infarction, stroke, sepsis) and chronic states (neurodegenerative disorders, in particular, Alzheimer's, Parkinson's and Huntington's diseases) [3]. Inflammatory caspases are essential in modulating inflammation and inflammatory conditions, such as psoriasis, arthritis, sepsis, etc. Inflammation and cell death are also key players in the pathogenesis of many metabolic diseases, such as obesity, diabetes, and liver disease [4]. Thus, caspases are attractive targets for the treatment of neurodegenerative and metabolic disorders, cancer, and inflammation.

All caspases share several distinct features. These include the catalytic triad residues, consisting of the active site Cys285, a part of the conserved QACXG pentapeptide sequence, His237, and the backbone carbonyl of the residue 177 (caspase-1 numbering). A striking feature of the caspase family is its specificity for substrate cleavage after an Asp residue, which is unique among mammalian proteases [5].

Figure 1. Caspases in cell death pathways [6].

Figure 1. Caspases in cell death pathways [6].

Figure 2. Caspase-mediated inflammatory responses [6].

Figure 2. Caspase-mediated inflammatory responses [6].

Caspase Focused Library by 2D Similarity

This Screening Library was developed by a 2D fingerprint similarity search (Tanimoto index ≥ 0.75) against the reference set of about 20,000 biologically active compounds (IC50, Ki, etc., less than 10 μM, inhibition > 25 %) extracted from the ChEMBL database.

As a result, more than 13,800 compounds were obtained for such targets as:

Caspase-1
Caspase-2
Caspase-3
Caspase-4
Caspase-5

Caspase-6
Caspase-7
Caspase-8
Caspase-9

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Figure 3. Compound distribution of single protein targets within the Caspase Focused Library.

Representative screening compounds from the Caspase Focused Library by 2D Similarity:

Caspase Targeted Library by Topomer Search

A reference set of potent caspase inhibitors that were co-crystallized with corresponding proteins were first selected. The query features were created based on crystallographic conformations of the ligands. After that, the TopomerSearch (SYBYL-X) tool was launched for a preselected set of Life Chemicals screening compounds. Finally, compounds with unwanted structures were filtered away with in-house MedChem and PAINS filters.

Over 2,800 potential caspase modulators were identified, focusing on the key targets in the apoptosis signal pathway (the corresponding PDB entries are indicated in the parentheses):

CASP1 (RCSB PDB ID: 1RWX)
CASP2 (RCSB PDB ID: 1PYO)
CASP3 (RCSB PDB IDs: 2CNO and 2CNL)
CASP6 (RCSB PDB: 3OD5)

CASP7 (RCSB PDB: 3EDR and 2QL9)
CASP8 (RCSB PDB: 1QTN and 3KJN)
CASP9 (RCSB PDB: 1NW9)
Paracaspase (RCSB PDB: 3V4O)

Figure 3. Human caspase-1 in complex with 4-oxo-3-{6-[4-(quinoxalin-2-yloxy)-benzoylamino]-2-thiophen-2-yl-hexanoylamino}-butyric acid.

Figure 4. Human caspase-1 in complex with 4-oxo-3-{6-[4-(quinoxalin-2-yloxy)-benzoylamino]-2-thiophen-2-yl-hexanoylamino}-butyric acid.

Caspase Targeted Library by Docking

This Docking Set contains over 7,800 structurally-diverse molecules with potential activity against the following targets:

Caspase-3
Caspase-8

As caspases play an important role in many vital processes, they are, thus, extremely attractive targets for drug development. However, there are a number of problems with different types of caspase inhibitors, e.g. inadequate efficacy, poor target specificity, and adverse side effects [4]. For drug discoverers to overcome these hurdles, Life Chemicals has prepared a unique target library designed especially with the caspase-3 and caspase-8 in mind. This Library was created on the basis of complexes with selective non-peptide inhibitors, therefore it is aimed at singling out these particular compounds. Since only few non-peptide selective inhibitors of caspases are known today, their search is extremely acute.

Caspase-3

Caspase-3 is a thiol protease involved in the execution phase of apoptosis, and it is known to promote tumor recurrence and tumor angiogenesis [7-8]. Caspase-3 is a key mediator of apoptosis in neuronal cells and it is involved in the regulation of multiple neurodegenerative disorders [9]. Thus, caspase-3 is a relevant target in neurodegenerative diseases and cancer. In order to obtain potential non-peptide selective inhibitors, we carried out our screening according to the pharmacophore hypothesis based on the known complex of caspase-3 with a selective non-peptide inhibitor. This helped us to take into account the features of interactions in the binding site as much as possible.

Key features:

Method: Pharmacophore-based virtual screening
X-Ray data used: RCSB PDB ID - 1GFW
Filters used: no
Number of compounds selected: 3,572

Figure 4. Pharmacophore hypothesis based on the complex of caspase-3 with the inhibitor.

Figure 5. Pharmacophore hypothesis based on the complex of caspase-3 with the inhibitor.

Caspase-8

Caspase-8 is a thiol protease that is an initiator of extrinsic apoptosis, an inducer of necroptosis and pyroptosis [10]. Caspase-8 is also involved in the expression of inflammatory cytokines, activation of inflammation, protection against shock and microbial infection [11]. Thus, caspase-8 is a relevant target in inflammatory diseases [12-14] and cancer [15-16]. It is found to increase the severity of SARS-CoV-2 disease [17]. Therefore, caspase-8 inhibitors can be considered as potential drugs in the treatment of COVID-19. Since several amino acid residues are not identified in the reported structure of this caspase with a selective non-peptide inhibitor, the model of the spatial structure was completed according to the corresponding reference structure using the SWISS-MODEL. When performing ligand-protein docking, the features of interactions in the binding site with a non-peptide selective inhibitor were taken into account as much as possible.

Key features:

Method: glide ligand docking (standard precision)
X-Ray data used: RCSB PDB ID - 6PX9
Constraints: Arg258 (H-bond)
Filters used: no
Number of compounds selected: 4,363

Figure 5. Spatial structure binding site of the complex of caspase-8 with the lead docking molecule F0617-0416.

References:

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