Caspases are a family of cysteine proteases that play essential roles in apoptosis (programmed cell death), necrosis, and inflammation. Apoptosis is vitally important to maintain the body’s health condition by eliminating old, unnecessary, or unhealthy cells. 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). Thus, inhibition of caspase activity with the aim of reducing cell death and, hence, tissue damage is predicted to bring beneficial therapeutic results.
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.
To identify potential caspase inhibitors and apoptosis-related compounds, Life Chemicals has designed its Caspase Targeted Library using docking-based virtual screening.
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, TopomerSearch (SYBYLX) 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 structurally-diverse screening compounds with predicted caspase inhibiting activity were identified, focusing on the key targets in the apoptosis signal pathway (the corresponding PDB entries are indicated in the parentheses):
- CASP1 (PDB ID: 1RWX)
- CASP2 (PDB ID: 1PYO)
- CASP3 (PDB IDs: 2CNO and 2CNL)
- CASP6 (PDB ID: 3OD5)
- CASP7 (PDB IDs: 3EDR and 2QL9)
- CASP8 (PDB IDs: 1QTN and 3KJN)
- CASP9 (PDB ID: 1NW9)
- Paracaspase (PDB ID: 3V4O)
This Caspase Screening Library can be used for cell survival, proliferation, and apoptosis research in drug discovery projects dedicated to numerous pressing diseases and disorders.