The Quest for Bioisosteric Replacements

To help advance drug discovery projects, a new and validated search method is presented by which potential
bioisosteric replacements can be retrieved from a database of more than 700 000 structural fragments. The
heart of the search method is an optimized topological pharmacophore fingerprint which describes each
fragment as a combination of attachment points, hydrogen bond donors and acceptors, hydrophobic centers,
conjugated atoms, and non-hydrogen atoms. In the fingerprint the influence of the attachment point is enhanced
by giving it extra weight relative to the other descriptors. The Euclidean distance has proven to be the
optimum distance measure to compare the fingerprints in a database search. The performance of the
pharmacophore fingerprint based search method has been validated using more than 2200 bioisosteric fragment
pairs extracted in an unbiased procedure from the BIOSTER database. The true bioisosteric pairs have been
compared with pairs of random fragments originating from the WDI database. Normalized by the standard
deviation of the random pairs distance distributions, an excellent separation of true pairs from random pairs
was obtained for R-group fragments (2.2 standard deviation units) as well as for linkers (2.6 units) and
cores (2.6 units). The bioisoster search method has been implemented as an intranet application called IBIS
and is now routinely used by Organon researchers.