Well-resolved electron densities were observed for both compounds in WDR91_2 and WDR91_4, revealing binding to the same side-pocket nestled between two β-propeller blades of WDR91 (Fig ). The binding pocket is predominantly hydrophobic, formed by aliphatic residues, including L465, L467, L477, A459 and T547 (Fig ). In both co-structures, the cyano groups of compounds 2 and 4 form hydrogen bonds with the backbone oxygen of K461, while their amide nitrogens form hydrogen bonds with the backbone oxygen of T547 (Fig 3B ). These structures highlight the important roles of both the cyano and amide moieties, two functional groups shared by all confirmed binders. A comparison of the co-structures of WDR91 bound to compound 2 and a previously reported compound identified via DEL-ML (PDB ID: 8SHJ) revealed that both compounds bind to the same side pocket, with well-overlapping amide backbone structures (Fig 3F ).