Protein-protein interactions and academic bounties

Whistling's post on the neat article published by researchers at Sunesis Pharma on tethering as a strategy to discover caspase inhibitors reminded me of Jim Wells, who had come to give a talk at Emory a couple of months ago. Wells moved from being president of Sunesis to UCSF. At UCSF, he commands a formidable repertoire of resources, including NMR, X-Ray and High Res Mass, as well as synthesis and molecular biology facilities. Who in academia can compete with such an immense wall of capability? I am sure Wells must have been offered great incentives including these facilities at UCSF to facilitate his transition from industry to academia. His move is symbolic of the power that academia has now started to command. Part of this power no doubt comes from it being allowed to have patents on drugs, from which they can get considerable finances through royalties. My own advisor, Prof. Dennis Liotta, got Emory 500 million $ in royalties, as one of the co-discoverers of the anti-HIV drug Emtricitabine (Emtriva®). That is a good sign, because researchers would gladly move back into the intellectually more stimulating environment of academics, if they were also provided good incentives and facilities.

But coming back to the scientific side, Wells is one of the pioneers in developing small molecule inhibitors for disrupting protein-protein interactions, a notoriously tricky endeavor. Proteins can interact with other proteins in as many ways as small molecules can interact with them. Finding a protein-protein interaction is not simply a matter of finding a good complementary fit, but is much more complicated, because the protein essentially interacts with another protein through flexible maneuvering. Not only can it simply slide into a hydrophobic complementary site, but it can also catch hold of loops, causing immense conformational changes in them, and then only be in a comfortable position to dock with the other protein. Needless to say, programs which depend on rigid body protein docking often fail miserably, like ClusPro, which gave me horrendous results on my system. Also, proteins may not always dock in a theoretically optimum manner in real systems, but only in an orientation that is optimum to cause further action.

Protein-protein docking will remain a holy grail for both experimentalists and computational scientists, more so with the huge number of protein-protein interactions impliccated in diseases now. This whole discussion reminded me of two excellent reviews on protein-protein interactions, which give a succint view of the field.

1. Small-molecule inhibitors of protein-protein interactions: progressing towards the dream- Michelle R. Arkin, James A. Wells, Nature Reviews Drug Discovery 3, 301 - 317 (01 Apr 2004)

2. Strategies for Targeting Protein–Protein Interactions With Synthetic Agents- Hang Yin and Andrew D. Hamilton, Angewandte Chemie International Edition Volume 44, Issue 27, Date: July 4, 2005, Pages: 4130-4163