Obviously, the most exciting result from the previous sections lies in the identification We performed triplicate molecular dynamics runs on the promising new candidate (4), which binds closely to the cleft with one of its trifluoromethyl groups close to the catalytic Cys111 and the opposite end of the molecule close to Thr301 and Pro248. As with its parent compound, binding proved to be very stable and strong throughout all simulations (Figure ). In one of the simulations (Figure ), the portion of the molecule close to Thr301 proved to be quite mobile, but the overall binding still remained quite strong due to the constancy of the interactions between the other trifluoromethylbenzene and the portion of the cleft leading to the active site. ADMET predictions of the behavior of the candidate molecules, and comparisons to the experimentally-confirmed inhibitors (Table ) suggests that these candidates should be as soluble as the known inhibitors, and to have similar effects towards the main P450 monooxygenases. We were therefore extremely surprised to find that experimental measurement of the actual binding strength proved very disappointing (Table ), and invalidated the expected inhibition by the proposed molecules. Such a dramatic mismatch between WHAM-US predictions and experiment suggested that, in spite of the predicted strength of interaction between our ligands and protein, binding was actually prevented through competing interactions of the ligands with its environment. proposed, yet inactive, molecules: whereas the surface area of the initial cluster of twenty 15g molecules increased within 20 ns (which indicates substantial dissociation of the aggregate), the other compounds aggregated even further (Figure , panel A).