The average difference of the Mpro and CYP 3A4 scores is 25.5, approximately 3.9 kCal if 1 kCal per 6.5 is used. This high average can be problematic in the design of realistic drugs as very quick metabolism will result if it is much higher than the binding to the target protein. The difference of Nirmatrelvir is 13.8, which could be improved upon.