The structure of many receptors is unknown, and only information about diverse ligands binding to them is available. A new method is presented for the superposition of such ligands, derivation of putative receptor site models and utilization of the models for screening of compound databases. In order to generate a receptor model, the similarity of all ligands is optimized simultaneously taking into account conformational flexibility and also the possibility that the ligands can bind to different regions of the site and only partially overlap. Ligand similarity is defined with respect to a receptor site model serving as a common reference frame. The receptor model is dynamic and coevolves with the ligand alignment until an optimal self-consistent superposition is achieved. When ligand conformational flexibility is permitted, different superposition models are possible and consistent with the data. Clustering of the superposition solutions is used to obtain diverse models. When the models are used to screen a database of compounds, high enrichments are obtained, comparable to those obtained in docking studies. © 2007 American Chemical Society.