A novel procedure for docking ligands in a flexible binding site is presented. It relies on conjugate gradient minimization, during which nonbonded interactions are gradually switched on. Short Monte Carlo minimization runs are performed on the most promising candidates. Solvation is implicitly taken into account in the evaluation of structures with a continuum model. It is shown that the method is very accurate and can model induced fit in the ligand and the binding site. The docking procedure has been successfully applied to three systems. The first two are the binding of progesterone and 5β-androstane-3,17-dione to the antigen binding fragment of a steroid binding antibody. A comparison of the crystal structures of the free and the two complexed forms reveals that any attempt to model binding must take protein rearrangements into account. Furthermore, the two ligands bind in two different orientations, posing an additional challenge. The third test case is the docking of Nα-(2-naphthyl-sulfonyl-glycyl)-D-para-amidino-phenyl-alanyl-piperidine (NAPAP) to human &α;-thrombin. In contrast to steroids, NAPAP is a very flexible ligand, and no information of its conformation in the binding site is used. All docking calculations are started from X-ray conformations of proteins with the uncomplexed binding site. For all three systems the best minima in terms of free energy have a root mean square deviation from the X-ray structure smaller than 1.5 &8491; for the ligand atoms.