There The difference in score from Nirmatrelvir-Mpro to Nirmatrelvir-CYP 3A4 is 84.4-70.7 = 13.8. This is very large, approximately of 2.1 kCal in binding energy. GOLD PLP scores are dimensionless numbers representing the interaction of docked ligand to the protein; the rough correspondence between PLP score differences and energy differences is found by known calculations in terms of both and is roughly 6.5 PLP for 1 kCal of various molecules. The binding energy is important and biochemical terms of ligand in the on-/off-states of protein-ligand is important. In terms of k_D or on-off ligand binding fraction, 1 kCal is commonly referred to be a factor of 10, although this is not a linear or rigorous relation. Studies of the metabolism of Nirmatrelvir revealed that it doesn't last for long in the body. The liver enzymes are actively working fast with it. As a result, plasma concentrations of it decrease too rapidly. 2 possible solutions to maintaining sufficient presence to have an inhibitory effect on viral replication via the target Mpro are: 1) use higher and more frequent doses, 2) add an inhibitor to the garbage collection process by blocking the action of the CYP enzymes, in particular 3A4. Both have drawbacks: 1) unwanted interactions with other proteins, 2) blocking the liver enzymes from normal function could result in increased levels of other medications to the point of toxicity. Dose changes for either purpose obviously means more interactions with a variety of proteins, not only Mpro.