A question about scientific publishing

I don’t really pay enough attention to know whether this is a new thing and I should just be used to it or not but I just received a strange editorial decision from an ACS journal (J. Med. Chem.).  The reviewers recommendations were:

1 – publish after major revisions [direct cost to author = $0]

2 – publish in JCIM [direct cost to author = $0]

3 – publish after major revisions [direct cost to author = $0]


Hardly a ringing endorsement of the paper but the editor’s decision is a bit troubling and I have to admit I didn’t even know it was something the ACS did.

Editors decision – transfer to ACS Omega [direct cost to author = $2000]

Is this just a feature of publishing that I need to get used to?  Are ACS editors in anyway incentivised (even indirectly via internal promotion of these pay-to-publish journals) to transfer papers in this direction?

This feels like two very different models of what scientific publishing is for shoe-horned into one organisation.  And on this occasion its an organisation carrying the name of a learned society which I think ought to favour one of those business models over the other.

I would be interested to know if this is a common experience which I should just get used to or if this something to be worried about?  Am I missing something?


A question about scientific publishing

Science and Democracy; wake up and smell the brexit.

I have been intending to blog for a very long time about an article that I read last year concerning the public funding of science in the UK. Events of this summer reminded me of the article and crystallised some thoughts that I feel like getting off my chest. The article in question is by Prof. Athene Donald in the Guardian (I should confess a tenuous link to Prof. Donald in that she is currently head of the college I attended in Cambridge). The article is entitled “UK science is excelling, but are we funding the wrong projects?”

The tenor of the article is that “excellence”, as judged by the UK research councils, should be more important in deciding how funds are allocated than “geography” as championed by politicians. The politician in this case is George Osborne, former Chancellor of the Exchequer, not a man that I am particularly fond of. However, the attitude in the article is that a cosy bunch of scientists should be permitted to decide how public funds are spent and that scientists have been “bothered” because a democratically accountable politician has taken an interest in this spending. Indeed, Mr Osborne went so far as to be a very prominent and public campaigner for a particular institute and for science in the north-west of England more generally. I am afraid that attitudes like that expressed in the article, which seem to assume that scientists have some inalienable right to spend public funds and that the intrusion of democratic accountability into the process is a bad thing, are just one more contributor to the alienation of much of the population of the UK. Their response to scientists’ contribution to the brexit debate was a great big flick of the finger.

It is pretty clear that the research councils in the UK are a fig leaf to give a veneer of scientific excellence while avoiding the need for politicians to get involved in picking individual scientific projects. They provide an accountant’s sense that the UK taxpayer is getting value for money and in many senses, I am sure they are. While this seems reasonable for some of the funds, which will inevitably go towards smaller, more incremental pieces of research, the line in the article decrying the fact that the research councils are required “to make open-ended commitments to new Treasury-backed projects” is an outrage and an enormous missed opportunity. Taxpayers have every right to scrutinize how any public money is spent and to allocate it however they wish via democratically accountable politicians. To suggest otherwise is, at best, foolish. More importantly, this is a short-sighted, missed opportunity. We should be seeking political support to drive the prominence of science in the public consciousness; I would like the public to be encouraged to celebrate the great feats being undertaken by scientists in the UK and to see our politicians climbing over one another to champion the great science that we do in the UK. I fear that the system we have instead sees a closed group of self-congratulatory scientists supporting far too much work that the public would be unlikely to wish to fund and telling them that they must keep paying for the research but are not entitled to have a say. I think Charles I had much the same attitude and revisiting this article has made me sense the righteous indignation that must have driven the Parliamentarians that he faced. I will try and write something without reverting to references to the 17th century at some point soon…

Obviously the above represents my own personal views and not that of any of the institutions with which I may be affiliated.

Science and Democracy; wake up and smell the brexit.

Docking Screens for Novel Ligands Conferring New Biology

Recently, we discussed the paper “Docking Screens for Novel Ligands Conferring New Biology” by Irwin and Shoichet. The paper discusses improvements in docking methods and demonstrates how docking campaigns can help to find new ligand series and new chemistries that can help reveal new biology.

The paper includes an extensive list of available docking resources: different web resources, compound libraries and docking software, together with the brief description of their application.

The authors highlight the danger that often comes with using docking as a black box – there is a great chance of the “garbage in, garbage out” effect where bad input results in bad output. Even a method that is (deceivingly) as simple as docking requires a team of experts that can thoroughly analyse the results and come up with several different potential lead series from the whole output rather than allowing the algorithm to pick the few best scoring ones by itself.

Another point was made that is often overlooked – there is an overwhelming amount of literature describing “docking for docking’s sake”. These are campaigns that result in good in silico hits, but these hits are then never confirmed experimentally. The authors briefly discuss the link between the docking and experimental artifacts and emphasise the need for orthogonal testing which, in our opinion, is rarely seen in publications dealing with any computational method.

We think this is a great summary of available docking resources that points out pitfalls associated with the approach that will inspire users to approach docking in a more thoughtful manner. However, we do feel that the title, although appealing, does not do it justice. The paper focuses on much more than just case studies where new chemotypes reveal new biology and it certainly is a necessary read for anyone embarking on a docking campaign for the first time or an experienced medicinal chemist.


Docking Screens for Novel Ligands Conferring New Biology

Journal Club – A real-World Perspective on Molecular Design

During our recent Journal Club, we discussed the paper “A real-World Perspective on Molecular Design” by researchers from Roche. The paper presents 10 case studies where computational methods were successfully applied to different research projects. The examples are diverse enough to cover a broad spectrum of possible approaches that one may take when doing computational study. It provides a set of guidelines, a check list of computational things you can do that are compatible with short project deadlines and that can provoke further thinking and generate new ideas. It also reminds the users that although computational methods, by their nature, provide numerical values, these should be treated as a qualitative input to an ongoing project. Somewhat surprisingly, all the studies were given in a prospective manner, which rarely is the case with published computational approaches – this in a way highlights the real life, practical use.

However, it is not clear who the article is intended for: for the method users/developers it lacks depth and for experimentalists it might be overly simplified, giving the impression that these are simple approaches that work every time and which can solve anything. But, as we well know, the road to success is paved with failure. It’s a shame these failures are rarely recorded in public literature. The authors are users/developers of the methods, so we find it surprising that they consider further development of the methods useless, “further improvements in computational methods may then have less to do with science than with good software engineering and interface design”. We think that science will benefit from improvements in computational methods and vice versa. The two are tightly interlinked: there is no good software engineering without the good underlying science. However, good science can exist without good software, but good software can surely help the science.

Unfortunately, they mentioned just cases in which protein structures and ligand properties are well known. Earlier stages of molecular design lack that sort of information and thus might need implementation of different approaches, such as computationally more expensive tools that haven’t been mentioned in this perspective.

We also found that some of the words are not always used appropriately. Looking at following sentence ‘Sulfonamides are molecular chimeras, which are found to form hydrogen bonds as well as interact with unipolar environments within proteins.‘ it seems that rather then being a hybrid chimeric molecule, sulfonamides as described in the article are more of a Dr Jekyll and Mr Hyde type of molecule which can be either one or the other rather than being a bit of both at the same time. Quite what the authors really meant by unipolar is also slightly confusing; if they mean a single magnetic or electric pole (unipolar), this seems unlikely to be a feature of many protein binding sites, at least when getting in to the interesting detail!

Journal Club – A real-World Perspective on Molecular Design

Synthetic chemistry is for roundheads, medicinal chemistry should be for cavaliers

The last blog post on the subject of Roundheads and Cavaliers prompted me to reflect about how good I think the analogy is and whether it is useful. It eventually got me wondering about another, related subject that I have struggled to find the words to describe. This is the divergence between the mindsets of two sub-disciplines of chemistry: synthetic and medicinal chemistry. Although it may no longer show, my PhD training was in synthetic chemistry. One of the things that I enjoyed most during that period was the retrosynthesis challenge that would be set for the group. We would work in small groups to try and concoct a convincing synthetic approach to various fiendish molecules. These would then be presented to the rest of the group who would provide robust criticism of the proposed schemes – it was a terrifying undertaking for a first year graduate student but a satisfying thrill by the time I was finished. The great challenge was to have a synthesis that would get past the immense cumulative knowledge of a world-leading bunch of synthetic chemists. The whole session hinged on the transferability of reactions from one context to another. Those who knew the most detail from the literature would always “win” – and what is more, this was (almost always) because they could reasonably say that they knew what would work and what would not. Hence, their proposed syntheses could be better informed than everybody else’s and they could provide more informed critique of the other syntheses.

This is an appalling preparation for medicinal chemistry.

It has frequently shocked me to hear medicinal chemists pontificating about what will and will not work. It has too often felt like a delusion. Actually, that’s not quite right. In terms of stacking the odds in your favour, it is a pretty good idea to say that everything will not work. This makes medicinal chemistry ideal territory for self-satisfied Roundheads. But how unhelpful, how uninspiring. In an environment in which little is understood definitively, we require persistent sorts who can take the knocks of things not working as hoped and can pick themselves up and do it all again. A corrosive presence that will decrease the prospects of success is the one who can only tell you why they think something will not work or worse, the “told you so” sorts who don’t even make testable predictions. I fear that the puritanical roundheads of synthetic chemistry are all too often in this category. Is this really the best training for the random bittersweetness of drug discovery? What sort of training can we provide that will bring more joie de vivre to the undertaking, where do we find cavaliers and how do we train them?

Synthetic chemistry is for roundheads, medicinal chemistry should be for cavaliers

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.

Roundheads and Cavaliers in drug discovery