Evaluating docking approaches for prediction of cyclodextrin and cucurbituril host–guest complex structures

The accurate prediction of host–guest complex geometries is critical for structure-based affinity prediction and the rational design of macrocyclic carriers including cyclodextrins (CD) and cucurbiturils (CB). Here, we benchmark eight docking scoring functions to assess their reproduction of crystallographic structures and generation of thermally accessible poses suitable for ensemble-based analyses. Our results suggest that while docking functions – broadly intended for protein–ligand complexes – are generally limited by either their scoring function’s ability to capture orientation-sensitive interactions, or the effectiveness of their search algorithms to sample conformational space. These problems are compounded by host-specific challenges where CB complexation depends on complex electrostatic forces and CD guests may interact with through many equivalent hydrogen-bond sites. From these results, we propose a practical workflow for structure prediction, using an approximate scoring function for initial pose generation followed by higher level calculations for the pose refinement.