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Advances and applications in bioinformatics and chemistry : AABC (1)
Journal of chemical information and modeling (1)
PLoS ONE (1)
Totrov, Max (3)
Abagyan, Ruben (2)
Fernández-Recio, Juan (1)
Gay, Nick (1)
Grosdidier, Solène (1)
Marsden, Brian D. (1)
Raush, Eugene (1)
Rueda, Manuel (1)
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ALiBERO: Evolving a team of complementary pocket conformations rather than a single leader
Journal of chemical information and modeling
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.
Computer applications for prediction of protein–protein interactions and rational drug design
Advances and applications in bioinformatics and chemistry : AABC
In recent years, protein–protein interactions are becoming the object of increasing attention in many different fields, such as structural biology, molecular biology, systems biology, and drug discovery. From a structural biology perspective, it would be desirable to integrate current efforts into the structural proteomics programs. Given that experimental determination of many protein–protein complex structures is highly challenging, and in the context of current high-performance computational capabilities, different computer tools are being developed to help in this task. Among them, computational docking aims to predict the structure of a protein–protein complex starting from the atomic coordinates of its individual components, and in recent years, a growing number of docking approaches are being reported with increased predictive capabilities. The improvement of speed and accuracy of these docking methods, together with the modeling of the interaction networks that regulate the most critical processes in a living organism, will be essential for computational proteomics. The ultimate goal is the rational design of drugs capable of specifically inhibiting or modifying protein–protein interactions of therapeutic significance. While rational design of protein–protein interaction inhibitors is at its very early stage, the first results are promising.
protein-protein interactions; drug design; protein docking; structural prediction; virtual ligand screening; hot-spots
A New Method for Publishing Three-Dimensional Content
Marsden, Brian D.
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