Caspase Targeted Library

Caspase molecule is a very conserved class of protease-like molecules. Caspases are a family of cysteine proteases that play a crucial role in apoptosis (programmed cell death), necrosis and inflammation. The enzyme has several isoforms of structure, the most common of which are Caspase-2, Caspase-3. Clinical studies have shown that increased levels of cellular apoptosis and cysteinase activity are frequently observed at sites of cellular injury in acute (myocardial infarction, stroke, sepsis) and chronic states (neurodegenerative diseases, especially Alzheimer's, Parkinson's and Huntington's disease). Therefore, inhibition of caspase activity aims to reduce cell death, and the development of small molecule compounds that modulate CASP activity has significant therapeutic potential.

BOC Sciences can design a novel caspase targeted library to deliver various drug-like compounds with predicted inhibiting activity against caspase. Our well-designed caspase screening library can be used for cell survival, proliferation and apoptosis studies in drug discovery programs dedicated to many pressing diseases and disorders.

Application of Caspase

• Natural and synthetic caspase inhibitors can significantly reduce or even block apoptosis induced by a variety of stimuli
• Some caspase nockout animal models exhibit significant absence of apoptosis
• Caspases catalyzes the cleavage of numerous functional intracellular protein molecules, and these cleaved molecules can lead to apoptosis

Figure 1. Canonical caspase substrate-binding pocket. (Duclos, C.; et al. 2017)

Caspase Targeted Library Design

At BOC Sciences, two receptor-based approaches: pharmacophore screening and molecular docking are combined to build this library.

1. Firstly, we have selected a reference group of effective caspase inhibitors that are co-crystallized with the corresponding proteins. The query features are created based on the crystallographic conformation of the ligands
2. A diversity of pharmacophore models with different pharmacophore profiles and excluded volume combinations (on hydrogen atoms of the amino acid residues of the active center) are constructed using crystals of CASPs with their peptide-like inhibitors
3. The highest-score compounds obtained by pharmacophore screening are docked in the same crystal. The compounds are finally selected by docking score cut-off filtering. Moreover, inspection of intermolecular hydrophobic contacts and hydrogen bonds with residues at key active sites are available
4. Then, a set of pre-selected BOC Sciences screening compound libraries are used to be filtered
5. Finally, compounds with unwanted structures in the HTS compound library are further filtered out using our in-house filters
6. Our scientists have identified over 2,800 potential caspase modulators, focusing on key targets in the apoptosis signaling pathway: CASP1, CASP2, CASP3, CASP6, CASP7, CASP8, CASP9 and Paracaspase

Figure 2. Schematic representation of major intracellular trafficking pathways. (Duclos, C.; et al. 2017)

Caspase Targeted Library Characteristics

• High diversity over the screening set: mean Tanimoto > 0.85
• Favorable physicochemical parameters and solubility requirements
• No PAINS or toxic substances/unwanted functions: filtered by strict ‘Ro5-like’ physicochemical and most stringent in-house structural filters
• Bioactivity and safety confirmed by preclinical studies and clinical trials
• Structural diversity, medicinal activity, and cellular penetration
• Structural document, IC₅₀, and other chemical and biological data are provided
• All compounds are continually updated
• Compound cherry-picking service is provided

What We Deliver

• Delivered within 2 weeks in any customer-preferred format
• Powders, dry films or DMSO solutions formatted in vials, 96 or 384-well plates
• All compounds have a minimum purity of 90% assessed by ¹H NMR and HPLC
• Analytical data is provided

BOC Sciences provides professional, rapid and high-quality services of Caspase Targeted Library design at competitive prices for global customers. Personalized and customized services of Caspase Targeted Library design can satisfy any innovative scientific study demands. Our clients have direct access to our staff and prompt feedback to their inquiries. If you are interested in our services, please contact us immediately!