Discovery of novel cathepsin S inhibitors by pharmacophore-based virtual high-throughput screening

The cysteine protease cathepsin S (CatS) is involved in the pathogenesis of autoimmune disorders, atherosclerosis, and obesity. Therefore, it represents a promising pharmacological target for drug development. We generated ligand-based and structure-based pharmacophore models for noncovalent and covalent CatS inhibitors to perform virtual high-throughput screening of chemical databases in order to discover novel scaffolds for CatS inhibitors. An in vitro evaluation of the resulting 15 structures revealed seven CatS inhibitors with kinetic constants in the low micromolar range. These compounds can be subjected to further chemical modifications to obtain drugs for the treatment of autoimmune disorders and atherosclerosis.

The Role of Dignity in Equality Law: Lessons from Canada and South Africa

This paper examines the link made on occasion between the concept of dignity and substantive equality; it is further noted that dignity can have very different meanings in different contexts. While the notion of dignity does not often play a substantive role in the resolution of decisions, sometimes the underlying understanding of dignity does matter. However, in all cases, judges should avoid the temptation to rely on unarticulated value judgments or subjective notions of dignity. When judges make reference to dignity, they should articulate the values underpinning their conception of it.