Pseudo-receptor modeling: a new concept for the three-dimensional construction of receptor binding sites

Molecular design of small molecules intended to target a macromolecule generally utilizes one of two computational approaches: "receptor fitting" or "receptor mapping". A comprehensive strategy for the design of potent, selective and novel ligands for cell-bound receptors combines the two by means of "pseudoreceptor modeling". Definition of a refined pharmacophore model is the first step. A subsequent step involves the construction of a pseudoreceptor--an explicit molecular binding pocket--for the bioactive conformation of a series of ligands with high affinity for a particular receptor subtype. The receptor-mapping program "Yak" allows the construction of a peptidic pseudoreceptor around any single small molecule or molecular ensemble of interest. The fidelity of the approach is exemplified by application to the active site of the enzymes human carbonic anhydrase I and thermolysin, followed by comparison with their known X-Ray crystal structures.