Bioisosterism as a molecular diversity descriptor: Steric fields of single ''topomeric'' conformers

The comparative molecular field analysis steric field of a single ''topomeric'' conformer is introduced as a molecular diversity descriptor particularly useful for combinatorial chemistry involving variations around a fixed ''core''. Using this new descriptor, 736 commercially available thiols are divided into 231 bioisosteric clusters, whose compositions agree at least as well with medicinal chemical experience and intuition as do clusters derived from Tanimoto differences between 2D fragment occurrences. However, in practice topomeric steric fields complement 2D fingerprints, being the two most frequently useful descriptors yet found for neighborhood-based design of combinatorial libraries.