I flew into Boston last night to give a talk at Novartis. I had a great time there today. Donovan Chin (Senior Investigator at the NIBR) was my host. I had a lot of fun hearing about their interests in molecules that are also dear to our hearts. I am talking about peptide macrocycles. Scott Lokey of the UCSC was also here at Novartis last week. Scott is doing some trailblazing work trying to understand the cell permeability of cyclic peptides.

It is clear that the industry appetite to macrocycles is high, particularly with regard to gauging their complex stereochemical preferences… It is eye-opening to talk to people in industry who do this for a living. When I hear that docking a small molecule takes a couple of minutes (I refer to computational docking into a binding site of a protein target), whereas the same process for a macrocycle is close to 18 hours, I really wonder how anyone will get the “heavy lifting” (to use the language of Dr. Andrew Roughton, the COO of Encycle Therapeutics, a company I founded in 2012) done in this space. It is, nonetheless, a fascinating problem and we are going to deal with it heads-on as a community. Naively, I asked Donovan about why does it really matter to be “right” in a complicated maze of conformations that are differentiated by a fraction of a kcal/mol. However, it is important to keep in mind that this thing is additive… To use Donovan’s analogy, it is like walking in the streets of Paris (or any other city with a complex web of streets): one wrong turn and your mistake is exacerbated such that the “real destination” will never be found… If we have a cycle that is composed of (say) 8 amino acids – once you add all the rotors, it is easy to see that this is a tough problem to crack computationally.

We needed to have some beers at the end of this day and went to this place called “Catalyst” right next to MIT. My former student Tim Rasmusson, who works at Novartis, came out – it was cool to see him! He is doing great. I hoped Ben Rotstein and Zhi He might join us (former PhD students who are now doing their PDFs at Harvard and MIT, respectively), but they were busy. I am at the airport now and will blog about my protein crystals tomorrow. The data is in!