In silico assessment of potential druggable pockets on the surface of α1-antitrypsin conformers.

ABSTRACT: The search for druggable pockets on the surface of a protein is often performed on a single conformer, treated as a rigid body. Transient druggable pockets may be missed in this approach. Here, we describe a methodology for systematic in silico analysis of surface clefts across multiple conformers of the metastable protein α(1)-antitrypsin (A1AT). Pathological mutations disturb the conformational landscape of A1AT, triggering polymerisation that leads to emphysema and hepatic cirrhosis. Computational screens for small molecule inhibitors of polymerisation have generally focused on one major druggable site visible in all crystal structures of native A1AT. In an alternative approach, we scan all surface clefts observed in crystal structures of A1AT and in 100 computationally produced conform

SUBMITTER: Patschull AO 

PROVIDER: S-EPMC3348131 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature