Library design and virtual screening using multiple 4-point pharmacophore fingerprints.

The use of multiple potential 4-point three-dimensional (3-D) pharmacophores for the design of combinatorial libraries and for virtual screening is discussed. These 3-D pharmacophoric fingerprints can be calculated from both ligands and complementary to a protein site, with a common frame of reference, and can be very rapidly searched to identify common and different 4-point pharmacophoric shapes in compounds and protein sites. A new extension to the method for structure-based design is reported that uses the shape of the target site as an additional constraint. This enables the docking process, for example in library design and virtual screening, to be quantified in terms of how many, and which, pharmacophoric hypotheses can be matched by a compound or a library of compounds.