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Abstract

The prediction of the structure of host-guest complexes is one of the most
challenging problems in supramolecular chemistry. Usual procedures for docking
of ligands into receptors do not take full conformational freedom of the host
molecule into account. We describe and apply a new docking approach which
performs a conformational sampling of the host and then sequentially docks the
ligand into all receptor conformers using the incremental construction
technique of the FlexX software platform. The applicability of this approach is
validated on a set of host-guest complexes with known crystal structure.
Moreover, we demonstrate that due to the interchangeability of the roles of
host and guest, the docking process can be inverted. In this inverse docking
mode, the receptor molecule is docked around its ligand. For all investigated
test cases, the predicted structures are in good agreement with the experiment
for both normal (forward) and inverse docking. Since the ligand is often
smaller than the receptor and, thus, its conformational space is more
restricted, the inverse docking approach leads in most cases to considerable
speed-up. By having the choice between two alternative docking directions, the
application range of the method is significantly extended. Finally, an
important result of this study is the suitability of the simple energy function
used here for structure prediction of complexes in organic media.