Scaffold Hopping in De Novo Design. Ligand Generation in the Absence of Receptor Information

Abstract

We report here the de novo generation of chemotypes and scaffolds for the estrogen receptor, without use of the receptor structure in the assembly phase. Through use of ligand superpositions or a single bound conformation of a known active, a pseudoreceptor can be generated as a design envelope, within which novel structures are readily assembled. Many of these structures have high similarity to known chemotypes. Scaffold hopping is readily achieved within this pseudoreceptor, indicating the advantages of such an approach in discovery research.