title: Comparison of ultra-fast 2D and 3D ligand and target descriptors for side effect prediction and network analysis in polypharmacology.
abstract: OBJECTIVE
  Some existing computational methods are used to infer protein targets of small molecules and can therefore be used to find new targets for existing drugs, with the goals of re-directing the molecule towards a different therapeutic purpose or explaining off-target effects due to multiple targeting. Inherent limitations, however, arise from the fact that chemical analogy is calculated on the basis of common frameworks or scaffolds and also because target information is neglected. The method we present addresses these issues by taking into account 3D information from both the ligand and the target.
  
  
  METHODS
  ElectroShape is an established method for ultra-fast comparison of the shapes and charge distributions of ligands that is validated here for prediction of on-target activities, off-target profiles and adverse effects of drugs and drug-like molecules taken from the DrugBank database.
  
  
  RESULTS
  The method is shown to predict polypharmacology profiles and relate targets from two complementary viewpoints (ligand- and target-based networks).
  
  
  CONCLUSIONS
  The open-access web tool presented here (http://ub.cbm.uam.es/chemogenomics/) allows interactive navigation in a unified 'pharmacological space' from the viewpoints of both ligands and targets. It also enables prediction of pharmacological profiles, including likely side effects, for new compounds. We hope this web interface will help many pharmacologists to become aware of this new paradigm (up to now mostly used in the realm of the so-called 'chemical biology') and encourage its use with a view to revealing 'hidden' relationships between new and existing compounds and pharmacologically relevant targets.
authors.affiliation: Unidad de Bioinformática, Centro de Biología Molecular Severo Ochoa (CSIC/UAM), Madrid, Spain; Departamento de Ciencias Biomédicas, Universidad de Alcalá, Madrid, Spain.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Cortés-Cabrera
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Morris
authors.forename: Paul W
authors.initials: PW
authors.lastname: Finn
authors.forename: Antonio
authors.initials: A
authors.lastname: Morreale
authors.forename: Federico
authors.initials: F
authors.lastname: Gago
mesh_terms: D000818:Animals; D062126:Databases, Chemical; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D064798:Polypharmacology; D011487:Protein Conformation; D060066:Protein Interaction Maps / Q000187:drug effects*; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000378:metabolism; D015203:Reproducibility of Results; D018570:Risk Assessment; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D012984:Software; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear
keywords: adverse drug reactions; chemical fingerprints; drug targets; polypharmacology; side effects