TPDs: Two-Piece Drugs

v. 1.1 of 01-06-16 (minor rewordings)
latest version available at
by Markus Krummenacker

Recently, due to a consulting task with the start-up company Libraria, I got exposed to the world of pharmaceutical drug design more than ever before. In particular, I was made aware of the very stringent molecular weight requirements of viable potential drug candidates. Because mass-marketed drugs (by which pharmaceutical companies make their real money) are to be delivered as easily as possible, i.e. as a pill, absorption properties through the digestive tract and bio-availability are overarching constraints for viable drug candidates. Nowadays, a set of rules known as the Lipinski rules [1] [2] are commonly used as guidelines for determining which molecules might be acceptable drugs with respect to the oral bio-availability issues. It seems to me like the most awkward constraint is the harsh requirement for drug molecules to have a molecular weight of no more than 500 Daltons.

Additionally, I learned that another problem drug designers wrestle with is making the molecules not only bind their targets strongly, but to also make them very specific for their targets. Many classes of receptors and enzymes that have been the subject of inhibition attempts are members of extensive families of somewhat similar gene products. For example, there are numerous kinases and proteases in our genomes, and drugs should target only exactly one specific protein out of all these. If a drug is indiscriminant, it will likely cause all kinds of undesired side-effects, and could thus be very toxic. The problem I learned about is that it apparently is a very difficult task to make e.g. protease inhibitors sufficiently specific and discriminatory to become useful drugs. In order words, the potential for unwanted cross-talk is very high for drugs targetting these common protein families.

It struck me as obvious that such targetting problems would be prevalent, if drug designers are forced to only use molecules smaller than 500 Daltons, which really is not very large, certainly not compared to the proteins they need to interact with. Such small molecules simply do not have enough surface area to easily contain a sufficient number of distinguishing features that help with the specific recognition of the correct binding pocket, while at the same time excluding any other interactions. Several years ago, I thought about the issue of how much information might be encoded on a given amount of surface area on molecules, for a project that examined design rules for molecular building-blocks that might be used for building self-assembled complex nano-scale structures. And so it is quite clear to me that to increase drug specificity, every manner by which larger molecules could be brought to bear should be seriously considered.

Why not deliver a drug in more than one piece ?

The idea that crossed my mind at a pleasant dinner on 00-07-14 with some Libraria folks was that one should try delivering a drug in more than one piece, each of which satisfies the stringent bio-availability criteria, and which thus each would be below 500 in molecular weight. These separate components would find their way into cells as usual. Once there, they would re-constitute the final and active drug, which could thus be larger in size and thus correspondingly more specific, and probably would also be able to bind better with higher affinity.

For simplicity, I will assume that there are just two components to the drug in the initial attempts to get this idea to work, thus allowing up to 1k Daltons "worth" of molecular weight being brought to bear on a target inside a cell. A number of reconstitution mechanisms can be imagined:

It might be possible to get a multiplicative effect by using multiple component drugs, which goes beyond the linear improvement naively expected, corresponding to the increased aggregate molecular weight. Almost certainly, the design of such drugs is more complicated, not only because of the larger interaction area that needs to be made complementary, but also due to additional design work needed for the functionalities that would have to react to form the fully assembled drug. On the other hand, as it is very difficult to find viable drugs in the pharmaceutical industry using only the current, inadequately smallish molecules, if this approach can significantly increase the chances of delivering good enough specificity and affinity to boost the number of viable drugs, it could very well be worth the extra effort. For all we know, the improvement could be an order of magnitude.

[1] Lipinski, C. A. et al.
"Experimental and computational approaches to estimate solubility and permeability in drug discovery and developmental settings."
Advanced Drug Deliv. Rev. 1997, 23, 3-29.

[2] Lipinski, C. A.
Presented at the Fourth International Conference on Drug Absorption, Edinburgh, Scotland, June 1997.

I would like to thank Barry Bunin, Stephan Schuerer, Guillermo Morales, and Regine Bohacek for the interesting discussions I was allowed to have with them, which has led to this wild idea. Any dissatisfaction or disbelief regarding the TPD idea should be solely blamed on me, and not on the people I have acknowledged here. Intelligent feedback and suggestions are always welcome, and can be sent to

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