Phototrexate is the first photoswitchable inhibitor of the human dihydrofolate reductase. The inhibitor activity is due to the cis form of the drug, whereas the trans form is inactive. In Figure , the potential energy surfaces interpolating the S 0 /S 1 CX and the cis and trans conformers for phototrexate is shown. A comparison with allelectron MRSF-TDDFT and SF-TDDFT is added as reference on the same interpolated geometries, both leading to equivalent relative energies. Overall, the topology of the surfaces at the SF-TDDFT and MRSF-TDDFT with respect to SF-TDDFTB level are similar, but the energetics are only approximately reproduced by SF-TDDFTB. The ground-state differences are on average 13.1 kcal/mol, with a standard deviation of 7.10 kcal/mol. In the excited states errors are larger, of the order of 23.20 kcal/mol on average, with a standard deviation of 2.18 kcal/mol. The CX is found at around 112 • , whereas the cis and trans conformers exhibit a dihedral angle of 9 • and 176 • respectively.