I very much enjoyed reading a recent review or commentary by Michael M. Hann on the concept of "molecular obesity" and the failure of drug development. He argues that by introducing hydrophobic moieties into drug leads may lead to promiscuity of the molecule and ultimately toxicity, thus contributing to the premature demise of drug candidates. The article is a great read and very inspiring. Hann also presents some analogies between evolutionary terminology and molecular characteristics.
Reading that, I thought that maybe the best teacher is nature itself; why not look at natural products and their ClogP toxicity correlations? According to the logic of Hann, bigger lipophilic compounds should be toxic. Although I did not really do a thorough statistics I see another picture. The first thing to be said is that small lipophilic compounds like monoterpenes and sesquiterpenes are in fact relatively untoxic; compared to the amount of scaffolds produced. We have recently addressed the issue of terpenoids in pharmacology in a comprehensive review article in Natural Products Report (Maffei, Gertsch and Appendino, 2011). Thus, volatiles being small and highly hydrophobic are not a problem. What about larger lipophilic compounds in nature? Every day we ingest significant amounts of phytosterols and triterpenoids from plant food. Triterpenoids (which are already quite large with MWs around 500-600) and in part also bioactive, are not generally known to be toxic.
Thus, there seems to be no obvious correlation between "obese" natural products and toxicity, at least as far as I can see. Maybe the correlations put forward by Hann are also a result of the "good binder" paradigm in drug development where high affinity is aimed at. Maybe the lipophilicity increases bioavailability or pharmacodynamic properties for many compounds and then the high affinities previously put into that molecule are too harsh. Nature probably has selected for optimal molecular attack and optimal molecular defense at the same time; thus increased binding and increased detoxification. What would really be interesting is a causative correlation between lipophilicity and toxicity; however, nature may go another way and generally works through networks and network interactions (Gertsch, 2011). It would be interesting to carry out this study on toxicity and molecular obesity with natural products. Maybe the fat guys are not always the worst, maybe it's only the the really large fat guys that cause the problem. And anyway, rather be fat than a hydrocephalus ... (says the guy working with lipids).