In silico prospective study on designing mitogen-activated protein kinase (MAPK1) inhibitors with S4. The absolute binding free energy of interaction (∆G, the lower, the better) was determined via Umbrella Sampling. Values are reported as the average over three repeats, along with the corresponding standard deviation. De novo designs 1-10 are compared with the closest inhibitor from the finetuning set (selected based on Tanimoto similarity on extended connectivity fingerprints computed on scaffolds). The experimentally-determined inhibition of MAPK1 for compounds 11-16 (reported as constant of inhibition, K i ) are also reported.