Improvement of Nirmatrelvir so that interaction is increased with Mpro and decreased with CYP 3A4. In this work only Mpro was used in molecular evolution with a GA. The situation improves after using a multi-objective genetic algorithm. In Ligand MultiObj GA the small molecules are iteratively improved simultaneously using 2 fitness functions in the evolution, maximizing interaction with Mpro and minimizing with CYP 3A4.