title: ALiBERO: evolving a team of complementary pocket conformations rather than a single leader.
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.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rueda
authors.forename: Max
authors.initials: M
authors.lastname: Totrov
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008024:Ligands; D062105:Molecular Docking Simulation; D009010:Monte Carlo Method; D011485:Protein Binding; D011487:Protein Conformation; D054852:Small Molecule Libraries / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D008024:Ligands; D054852:Small Molecule Libraries