N-Sulfonyl dipeptide nitriles as inhibitors of human cathepsin S: In silico design, synthesis and biochemical characterization.

A library of cathepsin S inhibitors of the dipeptide nitrile chemotype, bearing a bioisosteric sulfonamide moiety, was synthesized. Kinetic investigations were performed at four human cysteine proteases, i.e.

First interchromosomal insertion in a patient with cerebral and spinal cavernous malformations.

Autosomal dominant cerebral cavernous malformations (CCM) are leaky vascular lesions that can cause epileptic seizures and stroke-like symptoms. Germline mutations in either CCM1, CCM2 or CCM3 are found in the majority of patients with multiple CCMs or a positive family history. Recently, the first copy number neutral inversion in CCM2 has been identified by whole genome sequencing in an apparently mutation-negative CCM family.

Mapping the S1 and S1' subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents.

The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. A series of 26 new compounds were designed, synthesized, and tested against the recombinant cruzain (Cz) to map its S1/S1´ subsites. The same series was evaluated on a panel of four human cysteine proteases (CatB, CatK, CatL, CatS) and Leishmania mexicana CPB, which is a potential target for the treatment of cutaneous leishmaniasis.

How Significant Are Unusual Protein-Ligand Interactions? Insights from Database Mining.

We present a new approach to derive interaction propensities of protein-ligand atom pairs from mining of the Protein Data Bank. To ensure solid statistics, we use a line-of-sight contact filter and normalize the observed frequency of hits by a statistical null model based on exposed surface areas of atom types in the protein-ligand binding site. This allows us to investigate which intermolecular interactions and geometries are found more often than expected by chance in protein-ligand complexes.

Promiscuous Ligands from Experimentally Determined Structures, Binding Conformations, and Protein Family-Dependent Interaction Hotspots.

Compound promiscuity is often attributed to nonspecific binding or assay artifacts. On the other hand, it is well-known that many pharmaceutically relevant compounds are capable of engaging multiple targets in vivo, giving rise to polypharmacology. To explore and better understand promiscuous binding characteristics of small molecules, we have searched X-ray structures (and very few qualifying solution structures) for ligands that bind to multiple distantly related or unrelated target proteins.