To further investigate agent 3D structural awareness, the predicted binding poses of one ligand from the top 10 compounds (based on total score) produced by the experiments shown in Fig. were analyzed (Fig. ). Docking against MK2, a serine and threonine kinase target for anti-inflammation, was performed using AutoDock Vina with RDKit and TautEnum. Structure-activity relationship (SAR) studies demonstrated interactions between the co-crystallized ligand and residues Lys 93 and Thr 206 are vital for potency. The generated ligand retains these interactions and is predicted to exploit an additional hydrogen bonding interaction with Asn 191 (Fig. ). The overlap between the reference and generated ligand suggests the latter as a plausible binding pose and represents a solution obtained using only free software. Similarly, docking against COX2, a target for anti-inflammation, was performed using Glide with LigPrep. SAR studies demonstrated the cis-stilbene motif and the phenylsulfonamide moiety are paramount for potency and selectivity over COX1, respectively. The latter is attributed to the smaller residue Val 523 in COX2 in place of Ile 523 in COX1 facilitating easier access to the binding cavity. The generated ligand retains the cis-stilbene backbone and the sulfonamide group, which is predicted to form hydrogen bond interactions with Leu 352, Ser 353, His 90, and Arg 513 (Fig. ). Notably, approved drugs against COX2 include Celecoxib and Valdecoxib which also contain the aforementioned structural features. Crucially, the predicted binding pose for the de novo compound overlaps significantly with the co-crystallized ligand which is another selective COX2 inhibitor (SC-558), yielding greater confidence in its plausibility. The same analysis was conducted for the GOLD, Hybrid, and rDock experiments shown in Fig. . Docking against HDAC2, a histone deacetylase, was performed using GOLD with RDKit and TautEnum. SAR studies demonstrated the interaction with zinc and large bulky groups that extend deep into the 'foot pocket' are important for potency. The generated ligands retain interactions with zinc and Gly 154 and overlaps significantly with the co-crystallized ligand (see Supporting Information Fig. ). In another experiment, we used Hybrid with LigPrep as a docking component to design compounds against retinoid X receptor alpha (RXRα), a vital component in nuclear receptors. The cocrystallized ligand, CD3254 is an agonist and binds by modulating the H12 helix into its 'active' conformation. While the generated ligands do not retain these interactions, their predicted binding poses are not in conflict with the required conformation of the H12 helix. On the other hand, a common interaction with Arg 316 which is formed by endogenous ligands such as 9-cis retinoic acid is retained by the generated ligands, although there is some precedent that its role to facilitate binding is not essential (see Supporting Information Fig. ). Finally, docking against thymidylate synthase (TS), responsible for converting deoxyuridine monophosphate (dUMP) into deoxythymidine monophosphate (dTMP) was performed using rDock with RDKit and TautEnum. The co-crystallized ligand is Tomudex, an approved drug which interacts with dUMP via stacking interactions and the quinazoline ring forms the only hydrogen bond interactions with Asp 218 and Gly 222 (see Supporting Information Fig. ) which are retained by the generated ligands. Overall, all REINVENT-DockStream experiments generated compounds that retain vital interactions and display excellent agreement with reference ligand binding poses, suggesting the agent learns implicitly 3D structural information (see Supporting Information Table for all REINVENT-DockStream experiments and Fig. for all selected binding poses).