Fragment-Based Design

LOx 2.0 is InhibOx's versatile and powerful fragment-based ligand design system. 

LOx constructs chemically diverse ligands by making use of fragments in Scopius-FSpace, the fragment library extracted from InhibOx’s Scopius-CSpace database of over 220 million conformations of commercially-available drug-like molecules and CCDC's Cambridge Structural Database (CSD) of crystal structures of small organic molecules.  It can be applied to the design of totally de novo ligands, or as a focused tool for deriving libraries with specific properties and with simple synthetic routes from commercially-available reagents.

 LOx builds molecules using a completely general 3D fitting algorithm which allows it to move beyond standard ‘two exit-vector’ linkers in order to construct molecules that fit any set of three or more atoms within an active site.

The development of HIV protease inhibitors provides a useful example case for the LOx 2.0 ligand design system. Using the known structure of one inhibitor (1HVK) LOx finds the core scaffold of a different inhibitor  that displaces an active site water molecule (1QBU); Amongst the hits are seven cyclic urea compounds (right). The 1HVK water which is displaced by the inhibitor in 1QBU is shown as a transparent CPK volume to show proximity to the carbonyl oxygen of the urea groups.