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.

‘Hearing Voices': Punishing women’s mental ill-health in Northern Ireland’s jails

Informed by primary interviews and observational research conducted by the authors with women prisoners in Northern Ireland, this article focuses on prison as an institutional manifestation of women’s powerlessness and vulnerability, particularly those enduring mental ill-health. It contextualises their experiences within continua of violence and ‘unsafety’. It also considers official responses to critical inspection reports and those of the Northern Ireland Human Rights Commission based on the authors’ research findings. Finally, the primary research demonstrates that three decades on from publication the first critical analyses of women’s imprisonment, the conditions of gendered marginalisation, medicalisation and punishment remain. This is brought into stark relief in the punitive regimes imposed on those most vulnerable through mental ill-health.