Molecular Docking Constraint Experiments. The PDK1 receptor crystal structure was obtained from the Protein Data Bank (PDB) with PDB ID: 2XCH. A receptor grid was generated in the Maestro GUI with two hydrogen-bonding constraints specified between the reference ligand and Ala 162. Ligand preparation and docking was performed using DockStream, which is integrated with REINVENT, facilitating parallelization over numerous CPU cores. 3D coordinates for all agent sampled compounds from the baseline RL and CL experiments were generated using LigPrep. Default parameters were used except for the pH tolerance range set to 7.0 ± 1.0 with Epik and a maximum of two stereoisomers kept per compound. Glide docking used Standard Precision (SP) with the followings settings: allow only amide trans isomers, allow up to 25 poses for post-docking minimization, apply strain correction, and apply enhanced sampling with a factor of 2. All baseline RL and CL experiments were allowed 300 production epochs, i.e., epochs that involve docking, for a reasonable allocation of computational resources and for a fair comparison between baseline RL and CL. The docking score transformation was chosen to encourage agent sampling of compounds that possess a more favourable docking score than the reference ligand (Supplementary Fig. ).