Modulators of Protein–Protein Interactions

Protein-protein interactions (PPI) play a crucial 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 molecules tend to bind. On the other hand, PPIs 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 an 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)

Dr. Prabhat Arya is developing a new chemical toolbox enriched with both Heterocyclic Compounds and Natural Products to tackle such issues from Dr. Reddy’s Institute of Life Sciences. This approach could create a 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 of overcrowded 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 the way towards discovering novel agents in this regard.

Key Concepts for Medicinal Chemists

Molecular recognition in biological systems occurs by the complementary non-covalent bonding between a receptor binding site and a ligand (e.g., drug molecule). The attached concepts, numbers, and formulae assist medicinal chemists in structural modification related to the drug-receptor binding.

Picture of Olympicene

Back in 2009, at the IBM Research lab scientists imaged, for the first time, the chemical structure of an individual molecule (pentacene) with unprecedented resolution, using technique they developed called noncontact atomic force microscopy. The same IBM team, has once again come up with an interesting image. This time they have imaged a new organic molecule, Olympicene.

Olympicene, gets its name because its five linked rings resemble the Olympic symbol. The compound is a powder, that is very sensitive to light. In fact, even with brief exposure it changes color. It is only 1.2 nanometers wide, or 100,000 times thinner than a human hair. This AFM technique could become a real structure-determination tool for organic chemist.

PhD student fellowships

The International Max Planck Research School (IMPRS) "The Exploration of Ecological Interactions with Molecular and Chemical Techniques" in Jena, Germany, invites applications for 6 Ph.D. fellowships.

The application deadline is June 29, 2012.

For detailed information about the IMPRS, Projects offered, and application requirements, @http://imprs.ice.mpg.de/.

Molecule vending machine

Nano-catalysis is a fast-growing field of chemistry, which involves the use of nanomaterials as catalysts for a variety of selective organic transformations. Nano-catalysis can be considered as a bridge between homogeneous and heterogeneous catalysis. Because of the high surface area of nanomaterials, the contact between reactants and catalyst increases dramatically, and they can operate in the same manner as homogeneous catalysts (homogeneous catalysis); at the same time, due to their insolubility in the reaction solvent, they can be separated out easily from the reaction mixture (heterogeneous). Only the molecules of certain sizes and chemical properties are selected and guided to the reaction centers, where they are efficiently transformed into the desired products.

Solid supports have the potential to house more than one metal and, hence, catalyze multiple types of bond constructions. Such “multifunctional” catalysts attained much attention due to several advantages over mono metal catalysts. The high selectivity of the nanocatalyst may help reduce the energy consumption required for product separation and waste disposal processes in chemical industries.