The S4 model previously pre-trained on ChEMBL was fine-tuned with the SMILES strings of 68 manually-curated inhibitors from ChEMBL, having an experimental constant of inhibition (K i ) lower than 1 µM on MAPK1. The last five epochs of the fine-tuned model were then used to generate 256K molecules designs per each T value, ranging from 1.0 to 2.0 with a step of 0.25). The designs were ranked and filtered via loglikelihood score (equation ( )) and similarity to the training set (see Materials and Methods for further details). The ten top-scoring molecules (1 to 10, Figure ) were considered for further characterization using MD simulations. As a reference for evaluation, we performed MD simulations also for the closest fine-tuning neighbor of the considered designs (compounds 11 to 16, selected based on scaffold Tanimoto similarity on extended connectivity fingerprints, Figure ). The absolute protein-ligand binding free energy (expressed as ∆G; the lower the stronger the predicted binding) for molecules 1-16 was computed via Umbrella Sampling (Table ). The computed ∆G values for known bioactive molecules have a good correspondence with experimental K i values from ChEMBL (Table ), confirming the va-Table :