Submission Details

Molecule(s):
Cc1ccncc1N(CC=O)C(=O)Cc1cccc(Cl)c1

PET-UNK-bbe8d7ff-1

Cc1ccncc1N(CC=O)C(=O)Cc1cccc(Cl)c1

3-aminopyridine-like Check Availability on Manifold View
Cc1ccncc1N(CC#N)C(=O)Cc1cccc(Cl)c1

PET-UNK-bbe8d7ff-2

Cc1ccncc1N(CC#N)C(=O)Cc1cccc(Cl)c1

3-aminopyridine-like Assayed Check Availability on Manifold View

Design Rationale:

The objective of the design is to assess the benefits of linking warheads that can reversibly form covalent bonds with the catalytic cysteine to the fragment-derived inhibitor X_2646. The two selected warheads would be expected to provide a good range of 'warhead affinity' for cysteine proteases such as cathepsins and cruzain. Having IC50 values for these two compounds could inform predictions for other warheads such α-ketoamides. The binding modes have been generated by manual manipulation of the model of the bound X_2646 ligand. I have uploaded some notes to figshare and a PDB file with potential binding modes can also be downloaded: https://doi.org/10.6084/m9.figshare.12440486.v1

Discussion: