title: Identifying Interactions that Determine Fragment Binding at Protein Hotspots.
abstract: Locating a ligand-binding site is an important first step in structure-guided drug discovery, but current methods do little to suggest which interactions within a pocket are the most important for binding. Here we illustrate a method that samples atomic hotspots with simple molecular probes to produce fragment hotspot maps. These maps specifically highlight fragment-binding sites and their corresponding pharmacophores. For ligand-bound structures, they provide an intuitive visual guide within the binding site, directing medicinal chemists where to grow the molecule and alerting them to suboptimal interactions within the original hit. The fragment hotspot map calculation is validated using experimental binding positions of 21 fragments and subsequent lead molecules. The ligands are found in high scoring areas of the fragment hotspot maps, with fragment atoms having a median percentage rank of 97%. Protein kinase B and pantothenate synthetase are examined in detail. In each case, the fragment hotspot maps are able to rationalize a Free-Wilson analysis of SAR data from a fragment-based drug design project.
authors.affiliation: Cambridge Crystallographic Data Centre , 12 Union Road, Cambridge, CB2 1EZ, United Kingdom.|Department of Biochemistry, University of Cambridge , Sanger Building, 80 Tennis Court Road, Cambridge CB2 1GA, United Kingdom.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Radoux
authors.affiliation: Cambridge Crystallographic Data Centre , 12 Union Road, Cambridge, CB2 1EZ, United Kingdom.|John Innes Centre, Norwich Research Park , Colney Lane, Norwich, Norfolk NR4 7UH, United Kingdom.
authors.forename: Tjelvar S G
authors.initials: TS
authors.lastname: Olsson
authors.affiliation: UCB , 208 Bath Road, Slough, West Berkshire SL1 3WE, United Kingdom.
authors.forename: Will R
authors.initials: WR
authors.lastname: Pitt
authors.affiliation: Cambridge Crystallographic Data Centre , 12 Union Road, Cambridge, CB2 1EZ, United Kingdom.
authors.forename: Colin R
authors.initials: CR
authors.lastname: Groom
authors.affiliation: Department of Biochemistry, University of Cambridge , Sanger Building, 80 Tennis Court Road, Cambridge CB2 1GA, United Kingdom.
authors.forename: Tom L
authors.initials: TL
authors.lastname: Blundell
mesh_terms: D001665:Binding Sites; D008024:Ligands; D056004:Molecular Dynamics Simulation; D010453:Peptide Synthases / Q000737:chemistry; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry
chemical_list: D008024:Ligands; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D010453:Peptide Synthases; C022318:pantothenate synthetase