The Ying and Yang of Drugs and Targets

Today is election day in the UK, and so it's ones duty to vote, and then spend the rest of the day thinking about just how cool science is.

I was thinking the other day on the train, that we don't always want drugs that are benign, of course we always want drugs that are safe and predictable in action; but mechanistically we sometimes want to do harm, kill a cell, wipe it out entirely - let's call these malign. Of course, this socially responsible expression of this desire to obliterate life with drugs is in the development of antibiotics (bacteria, viruses, fungi and parasites) and also anti-cancer agents. The other system we sometimes want to modulate to cause specific harm is via activation of the immune system - priming it to attack non-self (pathogen) cells, or that limbo-land of pseudo-self cancer cells.

Anyway, this thinking of drugs as either (simplistically) malign or benign was triggered by a mail from a new collaborator interested in antiparasite agents identified via drug repositioning. How could you come up with a prioritised and annotated set of current drugs (and their associated cognate targets) that are biased to killing certain cells?

There are many approaches to this problem, here is just one... Given that the majority of drugs try to do no harm, and restore normal function to the recipient, screening most 'benign' drugs would be expected a priori to do little. Do we really want to find a way to balance sugar metabolism in a plasmodium and cure it's diabetes? - of course not, so screening known antidiabetic agents is less likely to reveal a cidal phenotype.
  • sporadic binding of a non-cidal drug/target to a new cidal target in the pathogen.
  • a benign-malign target switch occurs - so a context (organism) dependent switch happens - a nice example here is the statins, which were first isolated and characterised as anti fungal natural products, and now of course are used as cholesterol lowering agents in humans. It’s left as an exercise for the reader to answer why statins aren’t used as antifungals.

There are exceptions to all such half-assed approximations. The two most obvious are

So, let’s have a high level go at classifying drugs as malign or benign in intent. I’m on a train, so it will need to be a quick and dirty approach…. Use the WHO ATC classification! Classes J, L and P ('Antiinfectives for systemic use', 'antineoplastic and immunomodulating agents', and 'anti-parasitic products, insecticides and repellents' respectively) are clearly enriched in malign drugs (and malign targets), and certain subclasses of other top level classes are also malign - e.g. D01, D06 and G01 for example. 

So, we can rapidly (and approximately) classify drugs into malign and benign classes using the ATC, and via simple extension produce sets of malign and benign targets. We can even address some of the more-likely benign to malign switches, for example using sequence similarity to identify similar architectures/mechanisms. As an example, quite a few antithelmintics work by binding to ion channels and causing paralysis, finding ATC classes of ion-channel blockers is straightforward.

Toodlepip, for ever, jpo!