Killing polyavians with a unistone: designing promiscuous drugs

Decapitate multiple avians by means of a single projectile (Kill many birds with a single stone)

There is an interesting review (doi:10.1016/j.sbi.2006.01.013) on the "rational" design of promiscuous ligands and drugs which target multiple receptors. The review tries to break with the current paradigm of drug discovery, that of highly selective and potent ligands targeting a single receptor. According to the authors, there is an addition to this paradigm of selective ligand design; instead, design promiscuous ligands that would modulate multiple targets and bring about the intended action. This may look like a somewhat suprising strategy, because we know that promiscuous ligands usually carry the risk of toxicity and off-target side effects. But the paradigm seems to be more subtle than that. Here are some points from the review that I found interesting:

1. Many drugs which were initially thought to be effective because of their selectivity are now recognised to be promiscuous, and perhaps effective because they are promiscuous. A most striking example is Gleevec. This way of thinking has also raised questions about kinase inhibitors in general; are they efficacious because of or inspite of their promiscuity?

2. In one study, it was found that the promiscuity of ligands inversely correlates with their molecular weight. This is not too surprising, considering that more complex ligands will have to fulfil multiple site interactions with the receptor, the probability of which will be lower than that for fewer points of interaction. To me, this also translates into the entropic difficulties of binding to receptors, with more complex ligands having to pay greater entropic penalties. Of course, 'more complex' in terms of higher molecular weight does not necessarily mean ligands with more rotatable bonds; it can just mean more flat rings. But the problem of multiple site interaction is still valid even for these. For nature, the best ligands would be those which have a highly favourable enthalpy of interaction with the receptor at a few well-defined points, without having to pay a high entropic cost. That is one of the reasons why so many of the potent molecules that nature has designed are small, planar, heterocyclic ligands. This concept also spills over into fields like kinase inhibitor design. For selective design, we usually try to strike some golden mean in terms of ligand complexity.

3. There are also promiscuous proteins, with the most well-known example being cytochrome P450. Tubulin is also a pretty promiscuous protein. Sadly, I don't think we really understand what features of a protein or ligand make it promiscuous. Hydrophobicity seems to be a common criterion, but the very word "common" indicates that it is spread across a wide range of protein and ligand classes. One interesting feature of another promiscuous protein, PXR, is that it seems to bind multiple configurations of the same ligand. I have always wanted to find an example of such a protein. Whether this is a strong criterion for promiscuity would be a very interesting proposition.

To me, it appears that promiscuity first of all is not as widely observed as we would think, especially in terms of ligand lipophilicity. Consider Taxol. To my knowledge, there is not a single protein other than Tubulin to which it binds so strongly, inspite of it being quite lipophilic. But clearly, lipophilicity itself cannot be a sufficient criterion for ligand promiscuity. Also, the high selectivity of taxol may be related to its relatively high molecular weight, with reference to the MW-promiscuity study. The point seems to be that although we know some examples of promiscuous proteins and promiscuous drugs, their general features seem not much different from other non-promiscuous molecules.

It seems then, that to have effective promiscuous drugs, what we need is not just rampant promiscuity but selective promiscuity (I know, sounds like an oxymoron). The way I think about it, it won't work if the drug is flagrantly promiscuous across diverse chemical classes. Simply throwing in a greasy compound into the cocktail of body chemistry may get you a wildly promiscuous inhibitor, but that would not be what you want for a drug.
Consider kinase inhibitors. We can almost take it for granted that an ideal, conpletely promiscuous kinase inhibitor that targets dozens of kinases across different classes cannot be made into a working drug. But one can think of a particular subset of kinases, intricately linked to each other through signal transduction pathways, very sensitive to modulation of each other and to modulation by small molecules, implicated in a disease such as cancer, and expressed in cancer cells constitutively. If, and this is a big if, one can design an inhibitor that will inhibit this unique chosen subset of kinases, then one could potentially have a very potent drug.

In light of the very selective and stringent promiscuity criteria above, I would think that if anything, it may be more difficult to design a truly potent and effective promiscuous inhibitor, compared to a highly selective inhibitor, except by serendepity. In the latter case, you have to selectively target one protein. In the former case, you may have to selectively target three of four proteins. That just sounds so difficult through rational drug design. Naturally, designing such inhibitors would entail an intimate understanding of signal transduction pathways.