VH298 is bound to the surface of VHL via multiple hydrogen bonds as well as hydrophobic contacts. A hydrogen bond network is established by the residues Tyr98 and His115 with the OH group of the central hydroxyproline of VH298, which further interacts with Ser111 and His110. The tert-butyl and cyclopropyl moieties of VH298 interact with Trp88 and Tyr112, located at the LHS binding pocket, and Phe76, Tyr98, Leu101, and Ile109 from the RHS region form hydrophobic patches with the biaryl motif of VH298. Two interactions of structural water molecules are of particular interest, one of Wat450 with the nitrogen of the cyano group and the tert-leucine carbonyl oxygen, the other of Wat406 with the cyclopropanecarbonyl oxygen mediating the contacts with the LHS residues Asn67, Arg69, and His115. The interactions with the LHS region and the hydrogen bond pattern of hydroxyproline appear better exploited than the interactions with the hydrophobic RHS pocket. Here, several hydrophobic residues such as Phe76, Tyr98, Pro99, Leu101, Ile109, and Trp117 provide ample opportunity to further enhance the binding affinity (Figure ). To further explore the nature of the binding site, we calculated molecular interaction fields (MIFs) and estimated the buriedness parameter to evaluate the accessibility of the binding site. In particular, the RHS region showed favorable interactions with the hydrophobic probe, and the buriedness contour confirmed the region surrounding the phenylene core to be capable of accommodating larger moieties (Figure ).