Roundheads and Cavaliers in drug discovery

OK, the title is probably not very accurate and I am sure that those more historically literate than myself will highlight why this is a bad analogy. Its also very UK-centric for which I apologise for indulging myself. However, I think it is a useful comparator to explain what I think is wrong with many of the bandwagons that go zooming by if you just wait around long enough in a drug discovery environment. Its not so much the roundheads as having a distinctive look or political grouping that is the source of the analogy I wish to draw but their puritan roots. In particular, it is the puritan tendency to tell people what they should NOT do and their propensity for banning things which is the basis of the comparison I want to make. Notably, they undid themselves by (amongst other things) banning things such as the various feasts and festivities and the vividly decorated public buildings that were some of the few sources of gaiety for many of the populace.

The comparator that I wish to make and which therefore, I think makes me a cavalier, is that there are too many people trying to tell drug discoverers what NOT to do but without providing any particularly useful guide to what they should do instead. I further speculate that, like the roundheads, this approach is wont to sap the joy out of drug discovery for many and ultimately is unlikely to spur the kind of creativity that we cavaliers think essential for success in this field.

Compound related metrics The first puritanical approach that I wish to highlight is that of the various drug discovery metrics and whatnot that sometimes get restyled rules (eg Lipinski’s rules, the rule of 3, etc). Other such metrics include ligand efficiency and lipophilic efficiency and the myriad related functions. My former manager, Pete Kenny, has critiqued many of these from a scientific perspective and others have challenged their rigour while their supporters have argued for their utility as well as their rigour. I should acknowledge that I have personally found lipophilic efficiency a useful guide for contextualizing compounds relative to one another and to be a thought-provoking concept. However, it is a very poor tool for suggesting what to do next. It is a much better tool for rapping me across the knuckles for daring to think about suggesting more lipophilic compounds.

Druggability (protein related metrics) In my research group, we have most enjoyable group meetings on a Friday afternoon at which, from time-to-time, we discuss journal articles. This week’s is a perspective by Kozakov et al. describing druggability. I was once more struck by the roundhead tendency of the approach. Targets can of course be undruggable but deluding ourselves into thinking that our understanding of biology and chemistry is so complete that we can predict this in advance using only the structure of the protein involved is not just puritanical but rather presumptuous too. The authors do not help themselves by mentioning that some druggability approaches consider HMGCoA-reductase to be undruggable. My main problem with this concept is that it tells you only what NOT to do and while I appreciate that drug discovery is an enterprise in which the resources available are unlikely ever to be great enough to take on all possible targets and approaches, this seems to allow no role for curiosity and the human delight in exploration. Indeed, if this is really a tactic for wrapping up a decision about resourcing as science then we really should avoid that – a resourcing decision is a resourcing decision and should not be disguised as something else.

Forbidden substructures I am aware that so far, you could read this article as me trying to tell you not to do things that tell you what not to do. To try and provide an illustration of what I hope is a more constructive (the word cavalier in this context might make me sound rash) approach to tackling roundheadism. I am sure many people working in drug discovery have come across those who would ban certain substructures, sometimes with good reason, but mostly based on extrapolating one or two bad actors to a whole class. I have heard tell of the banning of nitro groups and, of course, of aromatic amines. I was particularly vexed by the latter because I had been led to believe that the problem with aromatic amines is mostly a chemical one: they are transformed biochemically into reactive species but then undergo a purely chemical reaction with genetic material. I thought I understood chemistry and so presumed that the problem could be tackled logically. I think we demonstrated in a couple of examples in real drug discovery projects that this is correct and that you can find examples that retain all the “good” properties but which are significantly less risky from a DNA reactivity perspective (I put it no more strongly than that). I would far rather hear about interesting new ways to make logical (or illogical) progress in drug discovery than to hear new ways of telling people what not to do.

I think I will leave it at those three examples for now but expect to feel compelled to rant about further roundheadism in the not too distant future.

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Roundheads and Cavaliers in drug discovery