Two new docking programs FRED (OpenEye Scientific Software) and Glide (Schrödinger, Inc.) in combination with various scoring functions implemented in these programs have been evaluated against a variety of seven protein targets (cyclooxygenase-2, estrogen receptor, p38 MAP kinase, gyrase B, thrombin, gelatinase A, neuraminidase) in order to assess their accuracy in virtual screening. Sets of known inhibitors were added to and ranked relative to a random library of drug-like compounds. Performance was compared in terms of enrichment factors and CPU time consumption. Results and specific features of the two new tools are discussed and compared to previously published results using FlexX (Tripos, Inc.) as a docking engine. In addition, general criteria for the selection of docking algorithms and scoring functions based on binding-site characteristics of specific protein targets are proposed. Figure Enrichment factors obtained with FlexX, Glide and FRED docking engines in combination with different scoring functions for seven selected targets with highly variable binding sites