The rise and fall of rational drug design

I'll be taking a look at a thought-provoking article (which got me chuckling several times) on drug design by my good friend Brooke Magnanti in this blog post.  I've known Brooke for quite a few years and I'll start this post with some photos taken by her back in 1998 on a road trip that took us from Santa Fe to Carlsbad via Roswell and then to White Sands, the Very Large Array before returning to Santa Fe.  The people in these photos (Andrew Grant, Anthony Nicholls and Roger Sayle) also appear in Brooke's article and you can see Brooke reflected in my sunglasses. The football photos are a great way to remember Andrew who died in in his fiftieth year while running and they're also a testament to Andrew's leadership skills because I don't think anybody else could have got us playing football at noon in the gypsum desert that is White Sands. We can only guess what Noël Coward would have made of it all.

What Brooke captures in her article on rational drug design is the irrational optimism that was endemic in the pharma/biotech industry of the mid-to-late nineties and she also gives us a look inside what used to be called 'Info Mesa'.  I particularly liked: 

"The name Info Mesa may be more apt than those Wired editors realised, since the prospects of a paradigm shift in drug development rose rapidly only to flatten out just when everyone thought they were getting to the top."

However, it wasn't just happening in computation and informatics in those days and it can be argued that the emergence of high-throughput screening (HTS) had already taken some of the shine off virtual screening even before usable virtual screening tools became available. The history of technology in drug discovery can be seen as a potent cocktail of hype and hope that dulls the judgement of even the most level-headed. In the early (pre-HTS) of computational chemistry we were not, as I seem to remember the founder of a long-vanished start-up saying, going to be future-limited. In a number of academic and industrial institutions (although thankfully not where I worked), computational chemists were going to design drugs with computers and any computational chemist who questioned the feasibility of this noble mission was simply being negative. HTS changed things a bit and, to survive, the computational chemist needed to develop cheminformatic skills.

There is another aspect to technology in the pharma/biotech industry which is not considered polite to raise (although I was sufficiently uncouth to do so in this article).  When a company spends a large amount of money to acquire a particular capability, it is in the interests of both vendor and company that the purchase is seen in the most positive light. This can result in advocates for the different technologies expending a lot of energy in trying to show that 'their' technology is more useful and valuable than the other technologies and this can lead to panacea-centric thinking by drug discovery managers (who typically prefer to be called 'leaders'). In drug discovery, the different technologies and capabilities tend to have the greatest impact when deployed in a coordinated manner. For example, the core technologies for fragment-based drug discovery are detection/quantification of weak affinity and efficient determination of structures for fragment-protein complexes. Compound management, cheminformatics and the ability to model protein-ligand complexes all help but, even when used together, these cannot substitute for FBDD's core technologies.  Despite the promises, hype and optimism twenty years ago, so vividly captured by Brooke, small molecule drug discovery is still about getting compounds into assays (and it is likely to remain that way for the foreseeable future).

This is probably a good point to say something about rational drug design. Firstly, it is not a term that I tend to use because it is tautological and we are yet to encounter 'irrational drug design'. Secondly, much of the focus of rational drug design has been identification of starting points for optimization which, by some definitions, is not actually design. I would argue that few technological developments in drug discovery have been directed at the problems of lead optimization. This is not to say that technology has failed to impact on lead optimization. For example, the developments in automation that enabled HTS also led to increased throughput of CYP inhibition assays. One indication of the extent to which technological developments have ignored the lead optimization phase of drug discovery is the almost reverential view that many have of the Rule of 5 (Ro5) almost twenty years after it was first presented.  There is some irony here because Ro5 is actually of very limited value in typical lead optimization scenarios in that it provides little or no guidance for how the characteristics of Ro5-compliant compounds can be improved. When rational drug design is used in lead optimization, the focus is almost always on affinity prediction which is only one half of the equation. The other half of that equation is is free drug concentration which is a function of dose, location in the body and time. I discussed some of the implications of this in a blog post and have suggested that it may be useful to define measures of target engagement potential when thinking about drug action.

What I wrote in that blog post four years ago would have been familiar to many chemists working in lead optimization twenty years ago and that's another way of saying that lead identification has changed a lot more in the last twenty years than has lead optimization.  Perhaps it is unfair to use the acronym SOSOF (Same Old Shit Only Faster) but I hope that you'll see what I'm driving at.  Free drug concentration is a particular problem when the drug targets are not in direct contact with blood as is the case when the target is intracellular or on the 'dark side' of the blood brain barrier. If you're wondering about the current state of the art for predicting intracellular free drug concentration, I should mention that it is not currently possible to measure this quantity for an arbitrary chemical compound in live humans. That's a good place to leave things although I should mention that live humans were not the subject of Brooke's doctoral studies...