eprintid: 1405420 rev_number: 31 eprint_status: archive userid: 608 dir: disk0/01/40/54/20 datestamp: 2013-09-12 18:50:48 lastmod: 2021-10-20 23:55:35 status_changed: 2013-09-12 18:50:48 type: article metadata_visibility: show item_issues_count: 0 creators_name: Patschull, AO creators_name: Gooptu, B creators_name: Ashford, P creators_name: Daviter, T creators_name: Nobeli, I title: In Silico Assessment of Potential Druggable Pockets on the Surface of α1-Antitrypsin Conformers ispublished: pub divisions: UCL divisions: B02 divisions: C08 divisions: D09 divisions: G03 keywords: Humans, Molecular Dynamics Simulation, Protein Multimerization, Protein Structure, Quaternary, Protein Structure, Tertiary, alpha 1-Antitrypsin note: © 2012 Patschull et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PMCID: PMC3348131 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 conformers, mimicking the native solution ensemble. We assess the persistence, variability and druggability of these pockets. Finally, we employ molecular docking using publicly available libraries of small molecules to explore scaffold preferences for each site. Our approach identifies a number of novel target sites for drug design. In particular one transient site shows favourable characteristics for druggability due to high enclosure and hydrophobicity. Hits against this and other druggable sites achieve docking scores corresponding to a K(d) in the µM-nM range, comparing favourably with a recently identified promising lead. Preliminary ThermoFluor studies support the docking predictions. In conclusion, our strategy shows considerable promise compared with the conventional single pocket/single conformer approach to in silico screening. Our best-scoring ligands warrant further experimental investigation. date: 2012-05-08 official_url: http://dx.doi.org/10.1371/journal.pone.0036612 vfaculties: VFLS oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green article_type_text: Journal Article, Research Support, Non-U.S. Gov't verified: verified_manual elements_source: PubMed elements_id: 410493 doi: 10.1371/journal.pone.0036612 pii: PONE-D-11-19861 lyricists_name: Ashford, Paul lyricists_name: Nobeli, Irene lyricists_id: PASHF36 lyricists_id: INOBE75 full_text_status: public publication: PLoS One volume: 7 number: 5 article_number: e36612 pagerange: - event_location: United States issn: 1932-6203 citation: Patschull, AO; Gooptu, B; Ashford, P; Daviter, T; Nobeli, I; (2012) In Silico Assessment of Potential Druggable Pockets on the Surface of α1-Antitrypsin Conformers. PLoS One , 7 (5) , Article e36612. 10.1371/journal.pone.0036612 <https://doi.org/10.1371/journal.pone.0036612>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/1405420/1/journal.pone.0036612.pdf