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 consi
dered 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 i
dentification of potential replacements. The complete PDB was converted into a database comprising almost 300鈥?00 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.