Screening for Allosteric Competition Using High Throughput SPR

Summary:

Many proteins are known to possess conformationally dynamic structures that can be altered in the presence of native ligands, receptors, etc. and these conformations can be necessary for functional activity (1,2). This characteristic can be overlooked, however, in traditional drug discovery screening paradigms that search for direct (orthosteric) competitors or else are otherwise informationally limited in describing mechanism of action (MOA) when competition is observed. A screening approach that can more readily distinguish orthosteric competition from indirect (allosteric) competition presents key opportunities towards detecting therapeutically unique mAbs. Additionally, identifying unique epitope and MOA are essential for securing intellectual property rights and enabling successful commercialization. Although protein modeling can help to understand dynamic properties of a target, currently it does not possess the de novo power to routinely predict sites that may be therapeutically relevant from an allosteric perspective. To this end screening for allosteric modulators using epitope binning is an attractive way to potentially identify unique candidates that possess distinct MOA.