Before docking experiments with the 66 chemical structures that fit all of the pharmacophoric requirements were run, the structures were 2-Pyridylethylamine dihydrochloride properly functionalized according to the compound 2 substitution pattern. For example, the structure of compound 5 evolved to 59, and then the latter was docked. The same process was followed for all 66 selected molecules. A detailed analysis of the results obtained from the docking studies showed that only 19 out of the 66 compounds yielded a consensus response for the proposed binding pose and maintained the critical interactions reported above. Finally, an inhouse computational approach to polypharmacology, implemented as part of the compounds registration process, was applied to estimate off-target selectivity profiling for potential target compounds derived from the selected chemotypes. None of the proposed compounds had notable predicted promiscuity; consequently, all 19 scaffolds proceeded. The final step in the process, which involved two different timeconsuming analyses, therefore only focused on these 19 fragments. The last step involved the i) assessment of chemical feasibility based on the number of synthetic steps, critical reactions, etc. and their potential to ����open���� additional diversity points and ii) determining their IP position. The roadmap shown in Figure 7 graphically represents the strategic guide utilized to perform this project-oriented 2-Phenylmelatonin scaffold prioritization, a sequential stepwise process split into two phases: a) a comprehensive in silico systematic strategy, in which a variety of virtual screening approaches were used to navigate a fragment DB that capitalized on knowledge from experienced medicinal chemists, in-house generated information, reported data, etc. and b) a time-consuming manual analysis. Application of this fragment-hopping strategy provides an excellent platform to be routinely utilized in drug discovery projects. Where structural information was publically available, the stepwise process for the last part of the strategy described in Figure 2 was based on a comprehensive in silico approach, in which not only ligand-based virtual screening and computational approach to polypharmacology but also structure-based approaches were utilized to prioritize among proposed novel scaffolds. Through this prospective analysis of an actual case study, the impact that this fragment-hopping strategy had in a drugdiscovery program is exemplified. In looking for novel PIM-1 inhibitors, this strategy led us to a) compounds from a new chemically feasible series, where the primary activity was kept equipotent, b) a chemotype with good IP position, c) improvements in off-target selectivity and d) positive changes in pharmacokinetic parameters, mainly focused on in vitro metabolic stability in liver microsomes.