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ALiBERO: Evolving a Team of Complementary Pocket Conformations Rather than a Single Leader
- Source :
- Journal of Chemical Information and Modeling. 52:2705-2714
- Publication Year :
- 2012
- Publisher :
- American Chemical Society (ACS), 2012.
-
Abstract
- Docking and virtual screening (VS) reach maximum potential when the receptor displays the structural changes needed for accurate ligand binding. Unfortunately, these conformational changes are often poorly represented in experimental structures or homology models, debilitating their docking performance. Recently, we have shown that receptors optimized with our LiBERO method (Ligand-guided Backbone Ensemble Receptor Optimization) were able to better discriminate active ligands from inactives in flexible-ligand VS docking experiments. The LiBERO method relies on the use of ligand information for selecting the best performing individual pockets from ensembles derived from normal-mode analysis or Monte Carlo. Here we present ALiBERO, a new computational tool that has expanded the pocket selection from single to multiple, allowing for automatic iteration of the sampling-selection procedure. The selection of pockets is performed by a dual method that uses exhaustive combinatorial search plus individual addition of pockets, selecting only those that maximize the discrimination of known actives compounds from decoys. The resulting optimized pockets showed increased VS performance when later used in much larger unrelated test sets consisting of biologically active and inactive ligands. In this paper we will describe the design and implementation of the algorithm, using as a reference the human estrogen receptor alpha.
- Subjects :
- Protein Conformation
General Chemical Engineering
Monte Carlo method
Library and Information Sciences
Crystallography, X-Ray
Ligands
Molecular Docking Simulation
Article
Small Molecule Libraries
Protein structure
Computational chemistry
Combinatorial search
Virtual screening
Binding Sites
Chemistry
Estrogen Receptor alpha
General Chemistry
Ligand (biochemistry)
Computer Science Applications
Docking (molecular)
Searching the conformational space for docking
Drug Design
Thermodynamics
Monte Carlo Method
Algorithm
Algorithms
Protein Binding
Subjects
Details
- ISSN :
- 1549960X and 15499596
- Volume :
- 52
- Database :
- OpenAIRE
- Journal :
- Journal of Chemical Information and Modeling
- Accession number :
- edsair.doi.dedup.....9ad926c56b66cd07a1990484a6d84ce4
- Full Text :
- https://doi.org/10.1021/ci3001088