The Crapshoot so far

The first phase of The Crapshoot is now complete and we will move on to other topics. To date we have looked at the properties of oral drugs and we'll take a quck look back at the journey so far.

Size and lipophilicity appear to be accepted as the most important determinants of a molecule's fate in its quest to become a Marketed Orally Active Drug. Hydrogen bonding, quantified either as a count of donors and acceptors or by the curious polar surface area, frequently makes an appearance in these discussions. However the connection between these properties and in vivo exposure is not particularly strong even if the trends are highly signficant. This appears to have prompted some unorthodox approaches to data analyis which, being simple folk, we admit to be being greatly confused by.

There are still many unanswered questions. Why does ionization not appear to be important in these analyses? Is octanol really the most approprate solvent with which to model the membrane interior or hydrophobic pockets in proteins? Why do hydrogen bond donors appear to be different to acceptors if it's all just desolvation? Should we use logP or logD to quantify lipophilicity?

The analyses of druglikeness reviewed in The Crapshoot to date have typically looked at property distributions in databases of drugs. Drugs can also be compared with non-drugs and we will review some of the relevant literature at some point in the future. At this point we simply suggest that our choices of non-drugs can influence our views of druglikeness.

Readers of this column may be familiar with the famous dictum of Ehrlich, "Corpora non agunt nisi fixata". Substances must bind for their effects to be observed and if you're into water memory and homeopathy we suggest that, for your education and edification, you read this post in Water in Biology.

Ehrlich's dictum could be seen as a first law of druglikeness and we are surprised that the requirement for binding is not explcitly stated more often in discussions on the subject. It is actually quite easy to design molecules with good aqueous solubility but getting these to bind where you want them to is rather more of a problem. If the natural ligand for your target protein is lipophilic, it is likely that a competitive ligand will also have to be lipophilic in order to compete. However, the natural ligand is unlikely to be inconvenienced by having to get from GI tract to plasma to cell to intracellular compartment. Are we blinkered by druglikeness when we should be thinking about drugability?

The focus of the Crapshoot will shift to the interactions between drugs and their targets, starting with a look at hydrogen bonding. The Blue Team and Red Team will return to their respective winter training camps to prepare for further gripping contests in the spring. We will return to the druglikeness theme at some stage, provided that we can bear ploughing through literature which, we are not ashamed to admit, does not set our pulses racing. For now, just see if you can spot any categorical sins in this recent review.