Combinatorial peptide synthesis

Yesterday we talked about a paper in journal club from Nature Chemical Biology. It was one of those combinatorial peptide synthesis papers--in this case to find a inhibitor of a protein in the clotting cascade (a serine protease that activated a precurser of a signalling cascade, I guess). It struck me that all these papers are the same. Do some combinatorial peptide (or peptide analog, or chemical altered peptide with some functional group sidechain), create a library of compounds, screen them, and try to find some compound that is an inhibitor or probe or whatever of some protein of pharmacological or biotechnological relevance. The targets change, the screening methods change, sometimes the synthetic methods change (although it's usually some variant of solid phase peptide synthesis). But the general idea stays the same: boring. There wasn't even any interesting structural biology about how the compounds worked as an inhibitor (my PI suggested that perhaps one of the moeities on a segment of the peptide blocked the catalytic triad--now that sort of hypothesis is something I can actually get into).

I guess I wouldn't be so judgmental about this research if it didn't seem like every issue of Nature Chemical Biology (or ACS Chemical Biology or Chemistry & Biology or ChemBioChem or what have you) had at least one article like this. In the introduction they always introduce their methodology as a novel (novel!?!) modular combinatorial method that is very promising as a way to find compounds of medicinal interest blah blah blah.

There's nothing that is really all that intellectually satisfying about this area of chemical biology to me. It's all the same. There's no narritive story to it--just hammering.

Combinatorial Chem

I've been reading about combinatorial chemistry lately, especially its applications in drug discovery. Last semester Jordan Katz (a Reed alum who recently finished his PhD) gave a talk about using a combinatorial approach to find the right inorganic materials for solar cells--unrelated to drug discovery, but showing that it is a useful technique in a variety of applications. This paper and this paper aren't exactly new, but they were my first introduction to the idea of screening a modular library that utilized a combinatorial approach (papers read in my topics in biochemistry course this past fall).

I think I understand the utility of such an approach. Biological systems are complicated, and the idea of design feels really...strange in some ways. Nature works through selection, not design. I know that there are drugs that have been designed, but I can see how a combinatorial approach would be a useful angle since there are so many potential compounds that could be pharmacologically active (is "chemical space" the right term?).

But every time I read a paper that uses a combinatorial approach, all I can think is how boring it must be for the poor grad student or lab tech carrying it out, since it's a conceptual problem that takes a lot of hands going through tedium to sort through. I think at an abstract level, design is more appealing because it is just more satisfying conceptually to think through a rational structure. At least, as a reader, it's more satisfying to read about. I can't help but find combinatorial chemistry boring, however useful of a tool it may be.