Stuart Schreiber and Paul Clemons of the Broad Institute have a provocative paper out in JACS on natural products and their use in drug discovery. As many know, a good part of the current pharmacopeia is derived from natural product lead structures, and in many other cases a natural product was essential for identifying a target or pathway for a completely synthetic compound.
But are there as many of these cases as we think - or as there should be? This latest paper takes a large set of interaction data and tries to map natural product activities on to it. It's already know that there are genes all up and down the "interactome" spectrum, as you'd expect, with some that seem to be at the crossroads of dozens (or hundreds) of pathways, and others that are way out on the edges. And it's been found that disease targets tend to fall in the middle of this range, and not so much in the too-isolated or too-essential zones on either side.
That seems reasonable. But then comes the natural product activity overlay, and there the arguing can start. Natural products, the paper claims, tend to target the high-interaction essential targets at the expense of more specific disease targets. They're under-represented in the few-interaction group, and very much over-represented in the higher ones. Actually, that actually seems reasonable, too - most natural products are produced by organisms as essentially chemical warfare, and the harder they can hit, the better. Looking at subsets of the natural product list (only the most potent compounds, for example) did not make this effect vanish. Meanwhile, if you look at the list of approved drugs (minus the natural products on it), that group fits the middle-range interactivity group much more closely.
But what does that mean for natural products as drug leads? There would appear to be a mismatch here, with a higher likelihood of off-target effects and toxicity among a pure natural-product set. (The mismatch, to be more accurate, is between what we want exogenous chemicals to do versus what evolution has selected them to do). The paper ends up pointing out that additional sources of small molecules look to be needed outside of natural products themselves.
I'll agree with that. But I suspect that I don't agree with the implications. Schreiber has long been a proponent of "diversity-oriented synthesis" (DOS), and would seem to be making a case for it here without ever mentioning it by name. DOS is the idea of making large collections of very structurally diverse molecules, with an eye to covering as much chemical space as possible. My worries (expressed in that link above) are that the space it covers doesn't necessarily overlap very well with the space occupied by potential drugs, and that chemical space is too humungously roomy in any event to be attacked very well by brute force.
Schreiber made a pitch a few years ago for the technique, that time at the expense of small-molecule compound collections. He said that these were too simple to hit many useful targets, and now he's taking care of the natural product end of the spectrum by pointing out that they hit too many. DOS libraries, then, must be just in the right range? I wish he'd included data on some of them in this latest paper; it would be worthwhile to see where they fell in the interaction list.