title: UFSRAT: Ultra-fast Shape Recognition with Atom Types--the discovery of novel bioactive small molecular scaffolds for FKBP12 and 11βHSD1.
abstract: BACKGROUND
  Using molecular similarity to discover bioactive small molecules with novel chemical scaffolds can be computationally demanding. We describe Ultra-fast Shape Recognition with Atom Types (UFSRAT), an efficient algorithm that considers both the 3D distribution (shape) and electrostatics of atoms to score and retrieve molecules capable of making similar interactions to those of the supplied query.
  
  
  RESULTS
  Computational optimization and pre-calculation of molecular descriptors enables a query molecule to be run against a database containing 3.8 million molecules and results returned in under 10 seconds on modest hardware. UFSRAT has been used in pipelines to identify bioactive molecules for two clinically relevant drug targets; FK506-Binding Protein 12 and 11β-hydroxysteroid dehydrogenase type 1. In the case of FK506-Binding Protein 12, UFSRAT was used as the first step in a structure-based virtual screening pipeline, yielding many actives, of which the most active shows a KD, app of 281 µM and contains a substructure present in the query compound. Success was also achieved running solely the UFSRAT technique to identify new actives for 11β-hydroxysteroid dehydrogenase type 1, for which the most active displays an IC50 of 67 nM in a cell based assay and contains a substructure radically different to the query. This demonstrates the valuable ability of the UFSRAT algorithm to perform scaffold hops.
  
  
  METHODS
  A web-based implementation of the algorithm is freely available at http://opus.bch.ed.ac.uk/ufsrat/.
authors: Centre for Translational and Chemical Biology, University of Edinburgh, Edinburgh, United Kingdom.
authors: Steven
authors: S
authors: Shave
authors: Centre for Translational and Chemical Biology, University of Edinburgh, Edinburgh, United Kingdom.
authors: Elizabeth A
authors: EA
authors: Blackburn
authors: Centre for Translational and Chemical Biology, University of Edinburgh, Edinburgh, United Kingdom.
authors: Jillian
authors: J
authors: Adie
authors: Centre for Translational and Chemical Biology, University of Edinburgh, Edinburgh, United Kingdom.
authors: Douglas R
authors: DR
authors: Houston
authors: Centre for Translational and Chemical Biology, University of Edinburgh, Edinburgh, United Kingdom.
authors: Manfred
authors: M
authors: Auer
authors: University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors: Scott P
authors: SP
authors: Webster
authors: Centre for Translational and Chemical Biology, University of Edinburgh, Edinburgh, United Kingdom.
authors: Paul
authors: P
authors: Taylor
authors: Centre for Translational and Chemical Biology, University of Edinburgh, Edinburgh, United Kingdom.
authors: Malcolm D
authors: MD
authors: Walkinshaw
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000465:Algorithms; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D022061:Tacrolimus Binding Protein 1A / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D022061:Tacrolimus Binding Protein 1A