Crystallographic and docking (Cathepsins B, K, L and S) studies on bioactive halotelluroxetanes

The molecular structures of the halotelluroxetanes p-MeOC6H4Te(X)[C(=C(H)X′)C(CH2)nO], X=X′=Cl and n=6 (1) and X=Cl, X′=Br and n=5 (4), show similar binuclear aggregates sustained by {· · ·Te–O}2 cores comprising covalent Te–O and secondary Te· · ·O interactions. The resulting C2ClO2(lone-pair) sets define pseudo-octahedral geometries. In each structure, C–X· · ·π(arene) interactions lead to supramolecular layers. Literature studies have shown these and related compounds (i.e. 2: X=X′=Cl and n=5; 3: X=X′=Br and n=5) to inhibit Cathepsins B, K, L and S to varying extents. Molecular docking calculations have been conducted on ligands (i.e. cations derived by removal of the tellurium-bound X atoms) 1′–3′ (note 3′=4′) enabling correlations between affinity for sub-sites and inhibition. The common feature of all docked complexes was the formation of a Te–S covalent bond with cysteine residues, the relative stability of the ligands with an E-configuration and the formation of a C–O· · ·π interaction with the phenyl ring; for 1′ the Te–S covalent bond was weak, a result correlating with its low inhibition profile. At the next level differences are apparent, especially with respect to the interactions formed by the organic-ligand-bound halides. While these atoms do not form specific interactions in Cathepsins B and K, in Cathepsin L, these halides are involved in C–O· · ·X halogen bonds

Theoretical insight into the mechanism for the inhibition of the cysteine protease cathepsin B by 1,2,4-thiadiazole derivatives

Several cellular disorders have been related to the overexpression of the cysteine protease cathepsin B (CatB), such as rheumatic arthritis, muscular dystrophy, osteoporosis, Alzheimer's disease, and tumor metastasis. Therefore, inhibiting CatB may be a way to control unregulated cellular functions and prevent tissue malformations. The inhibitory action of 1,2,4-thiadiazole (TDZ) derivatives has been associated in the literature with their ability to form disulfide bridges with the catalytic cysteine of CatB. In this work, we present molecular modeling and docking studies of a series of eight 1,2,4-thiadiazole compounds. Substitutions at two positions (3 and 5) on the 1,2,4-thiadiazole ring were analyzed, and the docking scores were correlated to experimental data. A correlation was found with the sequence of scores of four related compounds with different substituents at position 5. No correlation was observed for changes at position 3. In addition, quantum chemistry calculations were performed on smaller molecular models to study the mechanism of inhibition of TDZ at the active site of CatB. All possible protonation states of the ligand and the active site residues were assessed. The tautomeric form in which the proton is located on N2 was identified as the species that has the structural and energetic characteristics that would allow the ring opening of 1,2,4thiadiazole.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP