title: Identification of distant drug off-targets by direct superposition of binding pocket surfaces.
abstract: Correctly predicting off-targets for a given molecular structure, which would have the ability to bind a large range of ligands, is both particularly difficult and important if they share no significant sequence or fold similarity with the respective molecular target ("distant off-targets"). A novel approach for identification of off-targets by direct superposition of protein binding pocket surfaces is presented and applied to a set of well-studied and highly relevant drug targets, including representative kinases and nuclear hormone receptors. The entire Protein Data Bank is searched for similar binding pockets and convincing distant off-target candidates were identified that share no significant sequence or fold similarity with the respective target structure. These putative target off-target pairs are further supported by the existence of compounds that bind strongly to both with high topological similarity, and in some cases, literature examples of individual compounds that bind to both. Also, our results clearly show that it is possible for binding pockets to exhibit a striking surface similarity, while the respective off-target shares neither significant sequence nor significant fold similarity with the respective molecular target ("distant off-target").
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Marcel
authors.initials: M
authors.lastname: Schumann
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Roger S
authors.initials: RS
authors.lastname: Armen
mesh_terms: D001665:Binding Sites; D047390:Casein Kinase II / Q000737:chemistry / Q000187:drug effects; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000737:chemistry / Q000187:drug effects; D030562:Databases, Protein; D015195:Drug Design; D047629:Estrogen Receptor beta / Q000737:chemistry / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000187:drug effects; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000187:drug effects; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000737:chemistry / Q000187:drug effects
chemical_list: D047629:Estrogen Receptor beta; D008024:Ligands; D011506:Proteins; D011965:Receptors, Glucocorticoid; C066780:Clk dual-specificity kinases; C000588866:KDR protein, human; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D040301:Vascular Endothelial Growth Factor Receptor-2; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human