title: Subpocket analysis method for fragment-based drug discovery.
abstract: Although two binding sites might be dissimilar overall, they might still bind the same fragments if they share suitable subpockets. Information about shared subpockets can be therefore used in fragment-based drug design to suggest new fragments or to replace existing fragments within an already known compound. A novel computational method called SubCav is described which allows the similarity searching and alignment of subpockets from a PDB-wide database against a user-defined query. The method is based on pharmacophoric fingerprints combined with a subpocket alignment algorithm. SubCav was shown to be effective in producing reasonable alignments for subpockets with low sequence similarity and be able to retrieve relevant subpockets from a large database of structures including those with different folds. It can also be used to analyze subpockets inside a protein family to facilitate drug design and to rationalize compound selectivity.
authors: Novartis Institutes for Biomedical Research, Postfach, CH-4002 Basel, Switzerland.
authors: Tuomo
authors: T
authors: Kalliokoski
authors: Tjelvar S G
authors: TS
authors: Olsson
authors: Anna
authors: A
authors: Vulpetti
mesh_terms: D000818:Animals; D001665:Binding Sites; D057225:Data Mining; D062313:Databases, Pharmaceutical; D030562:Databases, Protein; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D063065:Organophosphonates / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D015203:Reproducibility of Results; D012984:Software
chemical_list: D018841:HSP90 Heat-Shock Proteins; D063065:Organophosphonates; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase