2. GPCR drugs: Magic bullets or magic "shotguns"? Over the last few years, the traditional paradigm of drug discovery laid out a century ago which posits that the ideal drug should be a "magic bullet" hitting a single protein target has been revised. While selectivity is still a valuable property, the importance of "selectively non-selective" drugs that hit a chosen subset of proteins is now much appreciated. No other family of drugs exemplifies this new paradigm more than CNS drugs which usually work by acting on a judicious set of GPCRs like those for serotonin, dopamine and norepinephrine. These compounds have been called "magic shotguns" and the general mechanism has been termed "polypharmacology".
However we are still light years away from actually designing such drugs which hit a pre-decided family of proteins on demand; a lot of the selective non-selectivity in these molecules has been designed in serendipitously and discovered in retrospect. The first step towards this goal would be to develop biochemical tools that would allow us to asses the exact polypharmacological activity of such compounds. UNC pharmacologist Bryan Roth details magic shotguns and efforts to unravel their complexities in a comprehensive review.
3. Directed evolution has been a valuable approach to speed up sluggish natural evolutionary processes to produce diverse libraries of biomolecules for functional screening. Here's a nice new review on using directed evolution to dissect protein-protein interactions which are of intense current interest.
4. And finally, a look at the human kinome and its interactions using a combination of sequence-based and ligand-based similarity methods. When each approach is limited, simply combine the two.