Macrocycles vs linear molecules: not a clash (yet)

As I get further and further into fragment-based screening using protein crystallography/small molecules, I have been developing ideas about a rational way of constructing linear oligomers of heterocycles. There will be way more on that in my future posts. But first, some people might ask: “What? You? Thinking about the virtues of linear compounds with your long-standing interest in macrocycles? What is going on?” Well, hear me out. I am not suggesting that we abandon some of our favourite peptide-based rings. No way, we are fully committed to the cyclic peptide deal and we will stand by them.

Having said that (as Larry David of “Curb Your Enthusiasm” would say – check it out:, there are some things to consider in terms of how we design our molecules to interact with protein targets. Here is something I mentioned at my lab’s meeting 2 days ago: we simply do not think about enthalpy hard enough. This is happening for a good reason: this is a tougher nut to crack. The history of drug discovery tells us that the first, and often most obvious, thing to do in an effort to make a molecule that selectively interacts with a protein target is to consider entropy. Macrocycles, of course, provide a gateway to address this problem. Researchers would typically consider a peptide ligand, identify their favorite beta turn or helix (think about stapled peptides), and then go on to make a cyclized version that hopefully recapitulates the bent epitope. But take a look at how drugs in a particular class evolve over the years. I suggest the following paper:

It is curious, isn’t it? Figure 1 shows (and rather emphatically) that the entropic contribution (which forms the basis for our instinctive thoughts about making macrocycles) dominates at the beginning, when first molecules in a given class are being discovered and developed. After some time, the sophistication increases and you can see how enthalpy contribution “grows”. The underlying reason is that enthalpy is more difficult to address. The reasons are manifold with solvation/desolvation sitting at the center stage. To sum up, I am not thinking about abandoning macrocycles. I am just under the influence of some of the fragment-based crystallographic work we are involved in and I think that we might often be better off improving the enthalpic contribution in our molecules when we consider linear shapes. I am falling in love with those.

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