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

P. Markt, Caroline McGoohan, Brian Walker, J. Kirchmair, C.L. Feldmann, G. De Martino, G. Spitzer, S. Distinto, D. Schuster, G. Wolber, C. Laggner, T. Langer

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)1693-1705
Number of pages13
JournalJOURNAL OF CHEMICAL INFORMATION AND MODELING
Volume48
Issue number8
DOIs
Publication statusPublished - Aug 2008

ASJC Scopus subject areas

  • Chemical Engineering(all)
  • Chemistry(all)
  • Computational Theory and Mathematics
  • Computer Science Applications
  • Information Systems
  • Library and Information Sciences

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