Identification of the bioactive structures of endogenous ligands that bind to receptors is important for the development of new drugs and other bioactive compounds. Crystal structure analysis of ligand-receptor complexes is widely used, but is inherently difficult for highly flexible ligands due to the presence of dynamic binding and unbinding equilibria. For example, many of the endogenous ligands of G-protein-coupled receptors (GPCRs) are structurally flexible lipid-based molecules, making it difficult to identify the bioactive binding conformations. Although changes in entropy terms such as solvation and the internal free energy of the interacting species contribute to ligand-protein binding, the direct interaction between the ligand and the protein is the most important factor for specific ligand binding. Three recognition models have been proposed so far: (a) the classical lock-and-key model, (b) induced fit, and (c) conformational selection. In the lock-and-key model (a), the unbound and bound states of the ligand and protein are the same, and there is no change in internal energy upon binding. In the other two models, (b) and (c), binding involves a conformational change in the ligand, the protein, or both. The idea underlying the conformational selection model (c) is that the free energy cost associated with conformational change is small for flexible molecules, and therefore the biologically active conformation is expected to be present in the "unbound" conformational ensemble.