title: Spherical harmonics coefficients for ligand-based virtual screening of cyclooxygenase inhibitors.
abstract: BACKGROUND
  Molecular descriptors are essential for many applications in computational chemistry, such as ligand-based similarity searching. Spherical harmonics have previously been suggested as comprehensive descriptors of molecular structure and properties. We investigate a spherical harmonics descriptor for shape-based virtual screening.
  
  
  RESULTS
  We introduce and validate a partially rotation-invariant three-dimensional molecular shape descriptor based on the norm of spherical harmonics expansion coefficients. Using this molecular representation, we parameterize molecular surfaces, i.e., isosurfaces of spatial molecular property distributions. We validate the shape descriptor in a comprehensive retrospective virtual screening experiment. In a prospective study, we virtually screen a large compound library for cyclooxygenase inhibitors, using a self-organizing map as a pre-filter and the shape descriptor for candidate prioritization.
  
  
  CONCLUSIONS
  12 compounds were tested in vitro for direct enzyme inhibition and in a whole blood assay. Active compounds containing a triazole scaffold were identified as direct cyclooxygenase-1 inhibitors. This outcome corroborates the usefulness of spherical harmonics for representation of molecular shape in virtual screening of large compound collections. The combination of pharmacophore and shape-based filtering of screening candidates proved to be a straightforward approach to finding novel bioactive chemotypes with minimal experimental effort.
authors.affiliation: Frankfurt Institute for Advanced Studies, Goethe University, Frankfurt, Germany.
authors.forename: Quan
authors.initials: Q
authors.lastname: Wang
authors.forename: Kerstin
authors.initials: K
authors.lastname: Birod
authors.forename: Carlo
authors.initials: C
authors.lastname: Angioni
authors.forename: Sabine
authors.initials: S
authors.lastname: Grösch
authors.forename: Tim
authors.initials: T
authors.lastname: Geppert
authors.forename: Petra
authors.initials: P
authors.lastname: Schneider
authors.forename: Matthias
authors.initials: M
authors.lastname: Rupp
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000097:blood / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000032:analysis* / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D057075:Enzyme Assays; D006801:Humans; D008024:Ligands; D012372:ROC Curve; D012015:Reference Standards; D012756:Sheep; D014584:User-Computer Interface
chemical_list: D016861:Cyclooxygenase Inhibitors; D008024:Ligands; D051546:Cyclooxygenase 2