To assess the effectiveness of our approach, we conducted protein-ligand interaction profiling, comparing the interactions of known scaffolds or the MYC MbIIIb peptide (Figure to 10D) with those hits generated through the Pocket Crafter workflow. Remarkably, our approach successfully generated molecules that exhibited similar interaction patterns to those observed in X-ray co-crystal structures. These generated molecules effectively engaged in all the key interactions with Ser223, Pro224, Asn225, Lys227, Lys272, and Leu288 on the WDR5 protein. Furthermore, the protein-ligand interaction profile generated from the top diverse chemotypes produced by our workflow facilitated the identification of all the key WDR5 residues involved in interacting with the MYC MbIIIb peptide (Figure ). This includes not only the residues that interact with known ligands (Pro224, Asn225, Lys227, and Lys888) but also additional residues (Lys250 and Glu289) that were previously unexplored in the hit molecules. These newly identified residues hold significant potential for the design of compounds that can effectively engage them as the stronger WDR5 binder, particularly in the context of competition with MYC MbIIIb peptide, for instance the optimization of WM-662 to WM-586 that can engage Lys250 significantly improved the potency in the SAR study of that scaffold series . Detailed interactions between the key residues and the top diverse hits selected from Pocket Crafter workflow are shown in Figure and the supplementary Table the Protein Ligand Interaction Fingerprints (PLIF) summary. This interaction histogram is generated with the residue-ligand interaction abundance percentage data from the PLIF tool in MOE using WDR5 tertiary structure (PDB: 8F1G) and top hit scaffolds. It summarizes the interactions between ligands and proteins using a fingerprint scheme. Interactions such as hydrogen bonds, ionic interactions and surface contacts are classified according to the residue of origin and built into a fingerprint scheme which is representative of a given database of protein-ligand complexes. Furthermore, it illustrates 3D view of all the top diverse hits in the pocket of WDR5 with hydrogen bond interactions in Figure (shown in green) with the key residues identified in Figure . Moreover, the protein-ligand interaction profile revealed another key WDR5 residue, Tyr 228, which interacts with diverse scaffolds generated through the Pocket Crafter workflow. This finding underscores the versatility of our approach in generating compounds that interact with diverse regions and key residues, thereby expanding the chemical space and offering new avenues for further exploration and optimization.