TPDs: Two-Piece Drugs

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:

• covalent connection forged by "abusing" some cellular enzyme:
  It ought to be possible to find some enzymatic reactions that are catalyzed inside cells, which could fuse the two drug components together. The two components would need adequate functional groups that could be processed by such enzymes. Apparently, a similar idea has been used in the past, using enzymes to cleave off special groups from "prodrugs", so that drugs can have functionalities that would make transport and bio-availability very difficult if they were not capped in this manner. However, the difference to TPDs is that "prodrugs" get smaller because something is cleaved off. The real trick would be to find suitable enzymatic reactions that join something, i.e. forge the two components of a drug together, such that the result is a larger object.
• covalent connection forged inside the receptor itself:
  If no suitable enzymatic reactions can be found that are "abusable" for forming the final drug, then the same effect could probably be arranged to happen within the targetted receptor cavity itself. Both components would have to bind the receptor separately, say in two adjacent pockets, such that the two components spend considerable time in close proximity. An otherwise slow reaction could be used to form a covalent link between the components, which results in the larger final drug, which would suddenly exhibit a much larger affinity than the separate pieces on their own. Each of the components would carry a functionality that would participate in such a slow reaction, which is unlikely to happen prematurely, because of the generally high dilution of the drug component molecules in bodily fluids (though the components might have to be delivered in separate pills). However, the receptor binding site increases the local concentration of these precursors by a large factor, probably by on the order of a million, allowing this bond formation to occur on a useful timescale. Functionalities that are usually not particularly reactive towards biological substrates could probably be used for this purpose, such as Diels-Alder components. Geometric changes that occur due to the reaction could also be designed to cause an "induced fit", pressing the drug further and deeper into the receptor.
• the components act independently:
  A slightly different game that could be played with a drug having several components is to not physically assemble a larger drug molecule, but to instead have the components act on separate targets, in concerted parallel manner, either by:
  • one binding the active site, and the other binding an allosteric regulatory site on the same protein. Depending on the particular situation and design, the allosteric mechanics that act on the active site could increase the affinity of the component binding there substantially. Combinatorial screening assays might find component pairs that might be surprisingly potent, compared to the individual components on their own.
  • the components binding separate proteins that are key bottle-necks in the same biological pathway
  The goal would be to obtain an aggregate improvement of drug performance by clamping down at several points in the same pathway, through the combined action of components which each on their own do not have the affinity and specificity that would ideally be desireable. This seems similar to the cocktails of drugs that have been used before, for stopping replication of the fast mutating HIV. But this concept could be applied much more broadly to less rapidly moving targets as well.

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

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