An interesting paper by Lumb and colleagues recently appeared in J. Med. Chem. By way of background, approximately 15 years ago, Brian Shoichet published a provocative article, in which he presented evidence that promiscuous inhibitors often work by forming aggregates:
http://pubs.acs.org/doi/abs/10.1021/jm010533y
This was a landmark paper because it unveiled a plausible cause of false positives in high throughput screening. The formation of such false positives had nothing to do with any special protein/small molecule interaction but was, instead, a non-specific effect. The community took this to heart and went a bit overboard, as we always do, seeing potential aggregators in all sorts of settings. Lumb and colleagues present evidence that aggregate formation and specific molecular level interaction may not be mutually exclusive. This work provides an example of aggregation-based inhibition of a protein–protein interaction involving tumor necrosis factor α. The reported capacity of small molecule ensembles to mimic protein surfaces is super cool. Unfortunately, the pdb file has not been released yet, so forgive me for not providing my usual pretty picture to accompany a structural biology post. You do have an option to see some nice views of the crystallographically characterized complex in the paper. There are 5 (!) inhibitor molecules that clump together into an aggregate in this crystal, replacing an entire protein subunit. I am not sure that there is a general lesson here, but I love seeing exceptions from the rules.
amphoteros 
this compound will pi-stack with itself like crazy, having combination of two electron deficient rings (aminopyrimidines) with electron rich biphenyl. Plus hydrogen bond on both ends. Developing this piece of varnish as medchem lead is utterly impossible. And I bet the PK is terrible – when injected, it would stick to every plasma protein it encounters, and be rapidly excreted in bile.
The reason why people would ever make crappy compounds like this one purpose, is most likely pharma metrics. Like in USSR, people are rewarded according to meeting the production quotas, regardless of the quality, by doing simple chemistry. And it is easy to boost potency by factor 3-5 by adding one extra ring…
About your statement..”Like in USSR, people are rewarded according to meeting the production quotas, regardless of the quality..” Why USSR? I worked in top pharma (top 3) in the US and in our medicinal chemistry program people will routinely submit -NBOC derivatives knowing fully well that they are “dead” compounds! I realized that they do to double their compound list so that they could be rewarded at the end of the year! Stupid management also played along for a while before they changed their metrics. IMHO people should be rewarded for making “few analogs and maximum impact” on a given program.
This is indeed true… The reason combichem died was that people became obsessed with meeting unrealistic expectations to deliver vast numbers of molecules for screening, but this naturally meant that the corresponding collections of the 90’s were skewed towards easy-to-make, boring compounds.
Shankaran: I have seen all kinds of breathtakingly bad management in US pharma – it persists because it is rewarded. Production quotas reminded me of growing up in Eastern Bloc, that’s why I mentioned it, but there is nothing inherently commie about them. It is just that the process of developing new drugs is so slow and responsibility for bad decisions is very hard to track, and the shareholders demand miracles and are willing to pay exorbitant salaries to execs who promise to deliver miracles. Of course these false cures will have bad consequences for the company but it benefits the slick and ruthless, you can re-organize research out of existence and save money without affecting the bottom line for the next 5+ years. This creates perfect conditions for wide-spread idiotic management behavior. With sharp enough elbows, it is easy to ruin a research program, present that as a great achievement and advance your pharma career by moving into another company, to a higher position.
Combichem: The whole thing was over-promoted to management folks who had only faint ideas what it takes to find and optimize a small molecule drug. The quality control was poor – it is not easy to ensure that a library containing say 100 000 compounds actually contains what it says it should, and false positive/false negatives really affected the screening. I worked for Selectide, one of the companies that started with bead-based mega-libraries. They belatedly noticed that parallel synthesis of small collections of compounds where each compound is purified by prep HPLC and re-confirmed by MS is the only reasonable way how to find anything by parallel synthesis/combichem. The megalibraries do not work for small molecules. By the way, they are sill in existence and their masters at Aventis like them – some of the peptidomimetic compounds could be only made by sold phase techniques, and the patent space for the screeening hits from their compound collections is less crowded as a result.
Indeed, this is a good point. We should create an index to relate the number of rotatable bonds to the ratio of electron-poor / electron-rich aromatic rings. Some math wiz can do it, I am sure. It might be called the “milkshake index”!