ChEMBL

It's a new year, so lots of planning to do, internship projects, PhD projects, etc. - so here's an idea, and you, dearest readers, can say if it's been done, or just plain stupid.

It's clear that in order to tackle new protein classes, especially for a more general approach towards protein-protein interactions (PPIs), that getting inhibitors with larger molecular weight into the body, and stable once there, is a big challenge. There's a lot of recent chatter on Teh Interwebs about the staped peptide approach, which ay well nt be as promising as once hoped. We know that there are some approximate limits to molecular weight, but to be able to get reliably up to a 800-900 MW range would and maintain good drug-like properties be a great thing. So what about achieving this with two co-dosed 400 MW inhibitors that "self assemble" in the target site to the fully effective ligand - just like in vivo fragment soaking (and just like the title of the Spice Girl's song above). The simplest way to think of achieving this would be through a targeted interaction between the two inhibitor halves, either via a direct interaction (but this will be of probable very low ligand efficiency and specificity) or maybe more interestingly - something like a specifically coordinated metal ion - like Zinc for example - there are many known biological system zinc coordinating ligands - but the simplest and most widely used is an imidazole.

%A B.A. Katz
%A J.M. Clark
%A J.S. Finer-Moore
%A T.E. Jenkins
%A C.R. Johnson
%A M.J. Ross
%A C. Luong
%A W.R. Moore
%A R.M. Stroud
%T Design of potent selective zinc-mediated serine protease inhibitors
%J Nature
%V 391
%P 608-612
%O http://dx.doi.org/10.1038/35422

In the mid 90's there was a lot of excitement in Pharma about zinc-mediated interactions with proteinases - involving a histidine in the target protein - I remember clearly the buzz around Arris' "Delta Technology". There was a Nature publication on this (reference above), and although it was clearly a real and interesting effect, it seemed to die as a drug discovery approach - my guess is because of the very controlled and very low "free" zinc ion concentration in vivo. So this is an example of a self assembled inhibitor - anyone aware of any other examples, theoretical approaches, etc. ?

Of course, there is the issue of safety and developability for two different agents, and of any DDI's between them, and of the temporal matching of the PK profiles, but as a strategy, is it sound, and are there some nice systems to try it on?