Abstract: The present invention provides methods of designing ligands that specifically bind to target molecules by testing a set of distinct compounds to identify compound that bind to member of a molecular family of interest. Those compounds that show binding activity can be used as a starting point for ligand design. Unlike previous methods, even compounds that bind with only low affinity are of interest and can be used. Common chemical structures of binding molecules including low affinity binding molecules are identified, thereby providing molecular scaffolds. Co-crystals of the protein and the molecular scaffolds can be formed and analyzed by X-ray crystallography to determine the orientation of the scaffold compounds at the binding site of the molecule.

Abstract: A method is disclosed for rational design of a PPAR, FXR, LXR-alpha, or LXR-beta antagonist comprising chemical modification of a PPAR, FXR, LXR-alpha, or LXR-beta agonist to: a) prevent formation of a hydrogen bond between the agonist and tyrosine or histidine, or tryptophan involved in receptor activation; and/or b) displace the tyrosine or histidine, or tryptophan involved in receptor activation from its agonist bound position. Preferably, little or no additional changes are made in the structure of the agonist so that the resulting antagonist is a close structural analogue of the agonist.