Comprehensive understanding of the interaction drivers of your compound
Benefits
Having a detailed understanding of the protein-ligand interactions will greatly facilitate lead generation and optimization. In particular, the identification of the anchoring fragments within the ligands will enable a more efficient optimization of low-potency screening hits. Due to its sensitivity, SPR biosensor-based analysis is uniquely positioned for measuring the associated low-affinity fragment-protein interactions. Identification of anchoring fragments withincompetitor’s lead compounds can also be beneficial for scaffold hopping.
Deliverables
1) What’s important for binding and what’s not
2) Identification of the anchor in the parent ligands
3) A preface of the binding site signature
4) An understanding of the energy contributions to binding
Technical Details
Parent ligands are analyzed and virtually deconstructed. Fragments able to adopt the conformation of the parent ligand are identified. Special care is taken to assure that no new pharmacophore features are introduced. Selected fragments are either purchased from commercial sources or synthesized. SPR biosensor-based determination of KD values are performed on fragments as well as on parent compounds. Binding site signatures are calculated and compared to signatures of other targets (see example in figure below).
Figure. A comparison between the HIV-1 RT NNRTI binding site signature described by FQ* (Fit Quality) with binding sites of Carbonic anhydrase and BACE-1. To make the differences more apparent, a trend line is added for each target. This line represents a moving maximum over three points.
