title: Binding mode similarity measures for ranking of docking poses: a case study on the adenosine A2A receptor.
abstract: We report an investigation designed to explore alternative approaches for ranking of docking poses in the search for antagonists of the adenosine A2A receptor, an attractive target for structure-based virtual screening. Calculation of 3D similarity of docking poses to crystallographic ligand(s) as well as similarity of receptor-ligand interaction patterns was consistently superior to conventional scoring functions for prioritizing antagonists over decoys. Moreover, the use of crystallographic antagonists and agonists, a core fragment of an antagonist, and a model of an agonist placed into the binding site of an antagonist-bound form of the receptor resulted in a significant early enrichment of antagonists in compound rankings. Taken together, these findings showed that the use of binding modes of agonists and/or antagonists, even if they were only approximate, for similarity assessment of docking poses or comparison of interaction patterns increased the odds of identifying new active compounds over conventional scoring.
authors.affiliation: Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstr. 2, 53113, Bonn, Germany.
authors.forename: Andrew
authors.initials: A
authors.lastname: Anighoro
authors.affiliation: Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstr. 2, 53113, Bonn, Germany. bajorath@bit.uni-bonn.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bajorath
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000737:chemistry*; D000465:Algorithms; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D043705:Receptor, Adenosine A2A / Q000737:chemistry*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D008024:Ligands; D043705:Receptor, Adenosine A2A
keywords: 3D similarity; Binding modes; Compound ranking; Molecular docking; Protein–ligand interaction fingerprints; Virtual screening