The CYP 3A4 cavity is a large featureless region that penetrates well into the structure. It doesn't have the structural features that typical target proteins have such as pockets, holes, valleys, and others. As a result it binds to generally anything and the question is how much. This largeness and featurelessness is the reason that the distribution has very wide peaks without much structure. While score can increase in lowering atom number in a cavity with lots of structure, generally with CYP 3A4 the more atoms the higher score. Nirmatrelvir has its highest score of 84.4, and it has 35 atoms (2.4 per atom). The particular state of Nirmatrelvir at highest score of 72.64 is an outlier in the histogram of docking runs, and that part of the distribution doesn't get any smoother with additional runs. First, it is the highest scoring conformer. Second, there are 11 out of these between 70 and 72.6. The ~3 score spread and discreteness gap in states is due to a strong physical restriction of binding. Binding in these poses is like flying a small plane into a mountain tunnel in high wind. It seems unlikely in thermal conditions for a ligand to bind there although possible. Physically there is a discrete ring rotation in the conformation that would make this conformer stick out from the continuous bumps at 68, 69 in Figure .