Bispecific Small Molecules
APPLICATION TO METABOLIC DISEASE
Our dual target approach is exemplified by the design of a bispecific small molecule that inhibits a novel combination of two metabolic disease enzymes from distinct gene families.
There was no precedence for a single molecule with integrated pharmacophore being able to bind to these targets.
The design process for a bispecific molecule is similar to our approach for single targets. The key difference is that potency must simultaneously satisfy two different targets.
The graph above depicts the evolution of a compound series to achieve the required potency whilst simultaneously maintaining selectivity, ADME, Ligand Efficiency and associated properties.
An early design exhibited nanomolar inhibition at both targets (Enzyme A: IC50= 347nM and Enzyme B: IC50= 11nM) and came from a series with opportunity for further refinement.
To understand how the same compound is able to bind two unrelated proteins both protein-ligand complexes were solved by x-ray crystallography (see below).