To address this short-coming, a GBGA is started again from the same starting population with a synthetic accessibility constraint to the score as described in section 2 which stears the search into an area of chemical space that is deemed to be more accessible. Virtually all molecules of the initial population are deemed to be synthetically inaccessible by the modified SA score, as shown in Figure . This is not surprising since it was developed for drug-like molecules. Within ten generations, the GA discovers new ligands that are deemed to have moderate synthetic accessibility as well as an energy difference within the desired target range. Here, a trade-off has to be made between the two components of the score, the energy difference and the modified SA score. Although molecules with modified SA scores of 1.00 are found after seven generations, the modified SA score of the best-performing molecule decreases again to 0.6 after ten generations since the energy difference of the molecule is closer to the target value of 27.55 kcal mol 1 which yields an increase to the overall score of 0.2. On the other hand, after 26 generations, the best-performing molecule has a less favorable energy difference than the best-performing molecule in the previous generation but this is compensated for by a higher modified SA score which yields an overall in- creased score of 0.1. After 30 generations, molecules with energy differences close to the target and near-perfect synthetic accessibility score are located.