Emulating Nature to Solve Intractable Targets
 
   
Unraveling the complexities of protein-protein interactions is a challenging task. Taking an entirely new approach, Serometrix developed the Peptimer™ Discovery Platform which identifies touch points critical to specific protein-protein interactions of interest. This rapid in silico screening process is predicated on the observation that many protein-protein interactions involve an induced fit conformational change, and many of these regions are found within surface regions involving unstructured loops.
 
 
Using first order backbone binding as the secondary structure motif at the core of most induced fit interactions, the first stage of the Serometrix platform performs a virtual fragmentation, denaturing, and binding (vFDB) assay on all fragments of the relevant proteins. These results are then quantified and analyzed for biological relevance.
   
   
Our induced fit supposition utilizes a key first order assumption - backbone binding is the secondary structure motif at the core of many conserved induced fit interactions. Therefore, the first stage of the Serometrix platform is to perform a vFDB assay on all fragments of the relevant proteins in the regulatory pathway. These results are then quantified based on their ability to virtually bind and form a beta sheet with all other segments. These results are then analyzed for biological relevance.
 
 

High scoring ligand/target pairs with apparent biological relevance are then molecularly modeled. Promising wild type ligands are then synthesized for in vitro testing. Based on experimental results, modified compounds employing natural and/or synthetic chemical moieties are then designed in an effort to learn more about the biomechanics of the induced fit interaction. This iterative theoretical and experimental process is repeated until the structure activity relationship is well understood. Entire families of compounds, and the associated IP around these families, may be created and optimized for activity, specificity, and drugability.

 

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This approach may also be used in many other instances to better understand protein-protein interactions in all of its complexity. It is proving to be especially valuable where good x-ray crystallography data is not available, for either the protein monomer, or its dimerized interaction. Serometrix is working with collaborators to demonstrate the power of this technology in these kinds of systems. For a very simple program overview of this approach, using well studied target with little commercial value, the following overview of the Arrestin technology demonstration project may be of interest.