Understand the interaction drivers of your compound
Benefits
Having a detailed spatial resolution of the protein–ligand interactions will greatly facilitate lead generation and optimization. In particular, the identification of the anchoring substructures within the ligands will enable a more efficient optimization of low-potency screening hits. Due to its sensitivity, SPR biosensor-based analysis with the Sprint™ platform is ideally suited for measuring the associated low-affinity protein- fragment interactions.
Deliverables
• Identification of anchor in parent ligands
• Partitioning of binding free energy of parent ligand to substructural moieties
• A preface of the binding-site signature important for correct ranking of fragment hits
Technical Details
Structures of parent ligands are analyzed and virtually deconstructed. Fragments estimated to be 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 using Beactica’s Sprint™ platform are performed on fragments as well as on parent compounds. Binding site signatures are calculated and compared to signatures of other targets.
Figure. Binding-site signatures expressed by corrected fit quality (FQ*) vs number of heavy atoms in ligand provide target-specific ranking measures. Examples show comparisons between the HIV-1 RT NNRTI binding site and the binding sites of carbonic anhydrase I and BACE-1. To make the differences more apparent, a trend line is added for each target. These lines represents a moving maximum over three points. The binding-site signatures tell that lower ligand efficiencies can be tolerated for fragment hits against HIV-1 RT or BASE-1 compared to hits against CA I. The profiles also show how to rank hits of different sizes against a common target.
