Hic Sunt Dracones: Molecular Docking in Uncharted Territories with Structures from AlphaFold2 and RoseTTAfold

AlphaFold2 and RoseTTAfold impress with their high accuracy
in
protein structure prediction. However, for structure-based virtual
screenings, not only the overall structure but especially the binding
sites need to be accurately predicted. In this work, the docking performance
for 66 targets with known ligands but without experimental structures
available in the protein data bank was elucidated. The results suggest
that using an experimental surrogate–ligand complex is often
superior over homology models, and only at low sequence identity to
the closest homologue AlphaFold2 structures show an equal performance.
The generally high fluctuation of receiver operating characteristic
area under the curve values obtained for different homology models
suggests that multiple combinations of docking programs and homology
models should be tested prior to prospective virtual screenings, and
in some cases post-processing of crude models might be necessary.