Monday, January 21, 2013

Modulators of Protein–Protein Interactions


Protein-protein interactions (PPI) play a key role in most biological processes. This nature of PPI has put forward itself as a prospective candidate for therapeutic intervention. Traditional small molecule target classes such as Enzymes, GPCRs, Kinases etc have a deep pocket (often used to bind an endogenous substrate), where small molecule tend to bind. PPIs on the other hand, appear to be too large and featureless for small molecules to bind against. Hence, due to this lack of well defined binding pockets, they were considered unsuitable/ extremely hard for targeting small molecules. 

Attempts at generating small molecule modulators of PPIs have been largely unsuccessful by adopting existing chemical techniques. This leads us to believe that we need to identify novel chemical space that can leverage the flat and expansive surfaces of PPI, which would in turn provide effective binding for small molecules. However, pharmaceutical companies are rather unwilling to add compounds containing multiple rings, multiple stereocenters that are highly complex, into their corporate collection as it does not align with their immediate short term business goals.

Heterocyclic
compounds
(aromatic, largely flat and hydrophobic)

+
Natural products
(rich in sp2 bonds)

=
Natural Product Inspired  
(New Chemical toolbox)

A new chemical toolbox enriched with both Heterocyclic Compounds and Natural Products to tackle such issues is being developed by Dr. Prabhat Arya from Dr.Reddy’s Institute of Life Sciences (Org. Lett., Article ASAP, DOI: 10.1021/ol3032126). This approach could create large 3D surface area, numerous binding interactions, rich stereochemical diversity, which would in turn solve the poor cell permeability of natural products, not to mention the added advantage over crowded IP Space.

The field of small-molecule-PP interactions appears to be highly promising, and in the near future, we can hope to see several strategies and techniques that will pave way towards discovering novel agents in this regard.

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