All fragments included in the databases had at least one ring and were annotated with the most relevant information, including the regiochemistry, the position for anchor points from which chemotypes can be functionalized, the number of diversity points, the number of fused rings, the molecular weight, the source, the phase and some other in silico estimated properties. Our library contains 42,168 unique compounds. In addition, our virtual CNIO library is composed of 10.8 million unique real compounds that are commercially available and/or reported. The combined libraries comprise the CNIO corporate database. The program described above was utilized to obtain the corresponding CNIO Onion0 and Onion1 fragment databases. Data mining was required to archive only those AC 5216 useful fragments for chemotype hopping. The following criteria were applied: chemical structures that bear at least one ring, that have a molecular weight between 60 and 300 and whose number of diversity points ranges from 1 to 4. The Onion0 CNIO corporate database contained 191,931 unique fragments fitting these criteria, and Onion1 was composed of 586,989 unique scaffolds. Finally, to define a target family related DB, in-house information from CNIO and the data from external databases, such as Kinase Knowledgebase, were utilized to build the kinase-oriented fragment DB. Once the three fragment databases were prepared, the projectoriented chemotype hopping began. Those chemotypes that may have fit better with reference substructure�Cthe fragments with one or two fused rings and two diversity points�Cwere selected from the Onion0 database. In total, there were 32,340 unique chemotypes. These fragments were utilized to build virtual libraries bearing as decoration those linkers and key substitutions illustrated in reference AC 4 substructure 4, methylamine and phenyl, as they may have an impact on the electrostatic characteristics of the main chemotype of the reference structure. Therefore, two potential virtual libraries were constructed. All the scaffolds from the Onion0 fragment DB that met the previously reported criteria were used to generate the corresponding Virtual Libraries : VLA, keeping methylamine at position R1 and phenyl at R2 and VLB, where phenyl will be born, in this case, at R1 and methylamine at position R2. Selection of R-groups to build these virtual libraries was based on the closest substitution pattern around the central cores from the reference compounds described in Figure 1; however, any R-group could be included in this analysis. These libraries were constructed using MOE software ; their generation occurs very quickly and can be completed within several seconds. To remove any compound with unwanted chemistry and any duplicates, a PipelinePilot protocol was built and run, thereby obtaining the final, project-based, virtual library from annotated fragments.