plexation, and ultimately leading to their application in drug delivery. Cyclodextrins such as bCD and its derivative HbCD are macrocycles composed of seven a-D-(+)-glucopyranose units linked via 1,4-glycosidic bonds. In general, the center and cavity of the host is hydrophobic and the primary and secondary hydroxyl group ends are hydrophilic (Figure ). In the case of HbCD, there are primary and secondary methoxy groups at both ends of the donut-shaped host instead of hydroxyls (Figure and 3). The guests for this dataset are 5 phenothiazine based drugs: Promazine (PMZ), Chlorpromazine (CPZ), Promethazine (PMT), Thioridazine (TDZ), and Trifluoperazine (TFP). (Figure ) Phenothiazines, particularly PMT, are widely prescribed in oral doses as an antihistamine and for sedation. The associated side effects of phenothiazines are described in the literature. bCD and HbCD can help stabilize and enhance the solubility of phenothiazines, and provide some controlled drug release to reduce toxic side effects. Computationally, these systems introduce some difficulties which can result in inaccurate BFE predictions for some methods, and are documented in literature. Due to the asymmetric structure of bCD and HbCD hosts, a host-guest complex can exist with the guest in the primary, secondary, and/or perhaps a "surface" orientation. The surface orientation is speculated to not be a true binding mode, but rather an unbinding event that may be necessary for a guest to flip orientation. Therefore, binding mode prediction of these complexes would be part of the challenge, and it is not always trivial even for systems like these which are assumed to be simpler. As shown in SAMPL7, a specific functionalization of bCD designed to orient a guest in a particular orientation did not always lead to the guest occupying that specific orientation. Previous experimental studies of bCD complexation with PMT 48 described a predicted binding mode with bCD, providing a starting point for this challenge. The other phenothiazines were expected to occupy a similar binding mode. In addition, some of the phenothiazines (CPZ, TDZ, TFP) have functionalization at the phenothiazine moiety, making the guest asymmetric. Thus, additional sub-orientations in each face may need to be considered or sampled.