For that we selected one scaffold from the data set analyzed in Part I as a core and attached varying R-groups at a common position. Each R-group was composed of functional groups present in the data set analyzed in the first part of the investigation. The R-groups comprised a linker attached to the core (Fig ) decorated with up to three terminal groups (Fig. ). Since in the prospective analysis experimental affinity measurements were not available, (A) For the library construction, one ligand scaffold was selected from the data set investigated in the Part I. The scaffold was combined with a set of linkers (Fig. ) and termini, using the chemical groups marked in red to form the covalent bonds. (B) Validation of binding free energies obtained with non-equilibrium free energy calculations against experimental results. we computed binding free energies of the ligands selected by the protocol of MD-based alchemical simulations, and trained the neural networks on the calculated affinities. Namely, we used non-equilibrium relative binding free energy calculations 14 based on Crook's Fluctuation Theorem (CFT) to find the free energy difference between each ligand of interest bound to the 4d09 crystal structure of PDE2 and a reference ligand with the same scaffold selected from the data set analyzed in Part I of the study. The description of hybrid ligand protein structures and topologies required for the alchemical calculations was constructed with the pmx 19 software. To calculate free energy difference between two compounds we performed equilibrium simulations at the physical end states and subsequently connected them with fast transitions driving the system from one end state to the other. The relative free energy difference was then recovered from the work distributions of the forward and reverse processes.