As a final case study involving a challenging binding site, we chose the HIV-1 intasome complex between HIV-1 integrase and the viral DNA prior to its integration with the host DNA . The inhibitor binding pocket lies at the junction between protein and DNA, and includes two magnesium ions which form essential interactions with integrase inhibitors. All HIV-1 intasome structures were determined by cryo-EM, but unlike µOR, the ligands pharmacophore is more defined. The RMSD results for these re-dockings and cross-dockings are shown in Figure . Once again, the matched guidance gives best re-docking performance (4/4, 100% vs 1/4, 25% unguided) while both matched and consensus density guidance give the same improved performance in the cross-dockings (16/24, 67% vs 12/24, 50% unguided). INSI XZ426 has an RMSD slightly larger than the success cutoff (2.00 Å) due to (a) the flexible and solvent-exposed hexanol tail which lies outside of the guidance density, and (b) the bifluorphenyl group, which is rotated by 180°with respect to the experimental pose (Fig. ). The consensus density guidance pose also flips the bifluorphenyl on IN-STI XZ446 (Fig. ). This docking also fails to pick up a known water-mediated hydrogen bond with the phenylsulfonyl, leading to this group being positioned in a subpocket rather than being more solvent-exposed. This region of the ligand is notably poorly covered by the consensus density. The oxadiazole of Raltegravir is similarly positioned into that same subpocket when cross-docked in PDB 6PUY (Fig. ). In the reference crystal structure of Raltegravir (PDB: 3OYA) it was possible to resolve an individual water molecule in the subpocket bridging the ligand-receptor interactions. This water was not resolved in any of the cryo-EM receptors used in the cross-docking but, if present, would have helped the correct placement of the ligand. Importantly, the magnesium and nucleic acid binding pharmacophores were correctly positioned even when the overall RSMD for ligands exceeded the >2 Å success cutoff.