title: Atom-Atom-Path similarity and Sphere Exclusion clustering: tools for prioritizing fragment hits.
abstract: BACKGROUND
  After performing a fragment based screen the resulting hits need to be prioritized for follow-up structure elucidation and chemistry. This paper describes a new similarity metric, Atom-Atom-Path (AAP) similarity that is used in conjunction with the Directed Sphere Exclusion (DISE) clustering method to effectively organize and prioritize the fragment hits. The AAP similarity rewards common substructures and recognizes minimal structure differences. The DISE method is order-dependent and can be used to enrich fragments with properties of interest in the first clusters.
  
  
  RESULTS
  The merit of the software is demonstrated by its application to the MAP4K4 fragment screening hits using ligand efficiency (LE) as quality measure. The first clusters contain the hits with the highest LE. The clustering results can be easily visualized in a LE-over-clusters scatterplot with points colored by the members' similarity to the corresponding cluster seed. The scatterplot enables the extraction of preliminary SAR.
  
  
  CONCLUSIONS
  The detailed structure differentiation of the AAP similarity metric is ideal for fragment-sized molecules. The order-dependent nature of the DISE clustering method results in clusters ordered by a property of interest to the teams. The combination of both allows for efficient prioritization of fragment hit for follow-ups. Graphical abstractAAP similarity computation and DISE clustering visualization.
authors: Small Molecule Discovery, Discovery Chemistry, Genentech, 1 DNA Way, 94080 South San Francisco, CA USA.
authors: Alberto
authors: A
authors: Gobbi
authors: Small Molecule Discovery, Biochemical and Cellular Pharmacology, Genentech, 1 DNA Way, 94080 South San Francisco, CA USA.
authors: Anthony M
authors: AM
authors: Giannetti
authors: Small Molecule Discovery, Discovery Chemistry, Genentech, 1 DNA Way, 94080 South San Francisco, CA USA.
authors: Huifen
authors: H
authors: Chen
authors: Small Molecule Discovery, Discovery Chemistry, Genentech, 1 DNA Way, 94080 South San Francisco, CA USA.
authors: Man-Ling
authors: ML
authors: Lee
keywords: Clustering; Command line program; Fragment screening; Hit prioritization; Similarity; Sphere exclusion