title: Pharmacophore fingerprint-based approach to binding site subpocket similarity and its application to bioisostere replacement.
abstract: Bioisosteres have been defined as structurally different molecules or substructures that can form comparable intermolecular interactions, and therefore, fragments that bind to similar protein structures exhibit a degree of bioisosterism. We present KRIPO (Key Representation of Interaction in POckets): a new method for quantifying the similarities of binding site subpockets based on pharmacophore fingerprints. The binding site fingerprints have been optimized to improve their performance for both intra- and interprotein family comparisons. A range of attributes of the fingerprints was considered in the optimization, including the placement of pharmacophore features, whether or not the fingerprints are fuzzified, and the resolution and complexity of the pharmacophore fingerprints (2-, 3-, and 4-point fingerprints). Fuzzy 3-point pharmacophore fingerprints were found to represent the optimal balance between computational resource requirements and the identification of potential replacements. The complete PDB was converted into a database comprising almost 300,000 optimized fingerprints of local binding sites together with their associated ligand fragments. The value of the approach is demonstrated by application to two crystal structures from the Protein Data Bank: (1) a MAP kinase P38 structure in complex with a pyridinylimidazole inhibitor (1A9U) and (2) a complex of thrombin with melagatran (1K22). Potentially valuable bioisosteric replacements for all subpockets of the two studied protein are identified.
authors: Computational Drug Discovery, CMBI 260, NCMLS, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors: David J
authors: DJ
authors: Wood
authors: Jacob
authors: J
authors: de Vlieg
authors: Markus
authors: M
authors: Wagener
authors: Tina
authors: T
authors: Ritschel
mesh_terms: D001384:Azetidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001596:Benzylamines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D030562:Databases, Protein; D015195:Drug Design; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: D001384:Azetidines; D001596:Benzylamines; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; C109573:melagatran; D048051:p38 Mitogen-Activated Protein Kinases; D013917:Thrombin