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