A tellurium-based cathepsin B inhibitor: Molecular structure, modelling, molecular docking and biological evaluation

The crystallographically determined structure of biologically active 4,4-dichloro-1,3-diphenyl-4-telluraoct-2-en-1-one, 3, shows the coordination geometry for Te to be distorted ψ-pentagonal bipyramidal based on a C2OCl3(lone pair) donor set. Notable is the presence of an intramolecular axial Te⋯O(carbonyl) interaction, a design element included to reduce hydrolysis. Raman and molecular modelling studies indicate the persistence of the Te⋯O(carbonyl) interaction in the solution (CHCl3) and gas-phases, respectively. Docking studies of 3′ (i.e. original 3 less one chloride) with Cathepsin B reveals a change in the configuration about the vinyl CC bond, i.e. to E from Z (crystal structure). This isomerism allows the optimisation of interactions in the complex which features a covalent TeSGCys29 bond. Crucially, the E configuration observed for 3′ allows for the formation of a hypervalent Te⋯O interaction as well as an O⋯HO hydrogen bond with the Gly27 and Glu122 residues, respectively. Additional stabilisation is afforded by a combination of interactions spanning the S1, S2, S1′ and S2′ sub-sites of Cathepsin B. The greater experimental inhibitory activity of 3 compared with analogues is rationalised by the additional interactions formed between 3′ and the His110 and His111 residues in the occluding loop, which serve to hinder the entrance to the active site.