Journal club: Deciphering the Fluorine Code – the many hats fluorine wears in a protein environment

This week, we enjoyed reading the Accounts of Chemical Research paper “Deciphering the Fluorine Code – the many hats fluorine wears in a protein environment” from the Koksch group in Berlin. Between the three of us, we have assorted reasons to be interested in the roles that fluorine plays when introduced to biological molecules. In particular, Yamir’s project involves him synthesising peptides with fluorinated amino acids in them.

We felt that the diagram in the abstract was a particularly good figure because it gave a good overview of the various factors that should be considered when introducing fluorine into a biological molecule. It highlights polarity, hydrophobicity, ring puckering, segregation (presumably by modulating the properties changes where the molecules populate) and secondary structure as underlying effects of fluorine and makes a great image by dotting illustrations taken from the relevant studies around the outside. There was also an interesting reminder about the gauche effect of fluorine. We discussed the origin of this effect. Although the orbital overlap a C-F bond anti-bonding orbital with the filled bonding orbital of an anti-periplanar C-H bond (see picture) would be preferred to that with the filled bonding orbital of a C-X bond (where X is O, N, F or other electron withdrawing group), it would be good to know how such effects play out in aqueous solution and in the environment of peptides: are they magnified or reduced? We think they are likely to be damped in these polar environments.

orb1vsorb2

We felt that in many places the discussion went into too much detail and lost sight of the general overview that might be hoped for in an Acc. Chem. Res. Paper. This was particularly noticeable in the section on Ribosomal Translation which had at once too much focus on detail but was not long enough to provide a full description of the details that the reader would ideally be given to appreciate this (remarkable) piece of work. We were amused by the “Section Summary” parts of the paper, particularly the one for the 4S-FPro and 4R-FPro in EGFP section where the section summary was longer than the section itself. We couldn’t decide whether these sections had been crowbarred in to placate reviewers or had been an idea that was included because it worked well for certain sections – it most certainly did not help in all sections.

We were intrigued by the section in which the stability towards protease action was discussed. It is asserted that fluorination stabilises the peptide in 25% of cases. This begs the question of what happens in the other 75% of cases. It is interesting to wonder whether the effect of fluorinating a peptide is any different to fluorinating a small molecule. In a recent cross-company data sharing exercise, we discovered that on average fluorine addition to aromatic rings has no effect on metabolism and wondered if the same thing is happening here with about 25% getting hydrolysed faster, 25% slower and 50% about the same. We also wondered if the focus on protease stability was too limited: are there other metabolic enzymes that process these molecules?

One of our frustrations with the article is that it deals only with the effect of fluorinating alkyl amino acids. We had hoped to find out more about fluorinating the aromatic, charged and polar amino acids but there was no relevant information in this article.   We also thought that the naming of these species did not help the reader to follow the article easily. Giving many of the non-natural amino acids labels which include “Gly” was very confusing, especially considering that no fluorinated glycine was involved.

Overall, it felt that the paper lacked an overall narrative flow and we wondered if this might be because many of these effects are still being unravelled and the complete understanding remains lacking in this area. We also thought that the paper could have more sensibly been half as long (and focused exclusively on overviews) or twice as long (maybe as two papers) to present enough detail on each of the interesting subjects to properly inform the reader.

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Journal club: Deciphering the Fluorine Code – the many hats fluorine wears in a protein environment

Journal club: Best practices of computer-aided drug discovery: lessons learned from the development of a preclinical candidate for prostate cancer with a new mechanism of action

We recently read the paper “Best practices of computer-aided drug discovery: lessons learned from the development of a preclinical candidate for prostate cancer with a new mechanism of action”. This made an interesting compare and contrast with a paper that we read some time ago from Roche in which various contributions of computational techniques to drug discovery were described. Overall, we felt that this paper (the Best practices… one) is more useful because it provides more depth and so there is a better chance of being able to apply the techniques and learning. However, the paper does not provide enough of the details concerning techniques, settings and practical tips to permit readers to easily reproduce the work. One of the aspects that was most enjoyable about this article is that it presents the story in a chronological fashion. While this may capture a route that is not as direct as it might be, it does provide the reader with a more realistic view of how these studies might play out in practice than the rather vaguer previous paper. We had a good discussion about AUC under the ROC curve values and what values of this parameter are desirable.

 

The key learning that is provided by the paper and which chimes with our own experiences is that there is great value in working closely with experimentalists. Among the recommendations provided in the final section we felt that “work closely with experimentalists during all stages of the project, learn from negative results and fine-tune your CADD pipeline on the basis of the wet-lab outputs” was particularly apposite.

Journal club: Best practices of computer-aided drug discovery: lessons learned from the development of a preclinical candidate for prostate cancer with a new mechanism of action

Chemistry in the UK – too important to accept such a large gender imbalance

I believe that chemistry and its related activities hold the key to great improvements in both the quality and quantity of human life. As a consequence, it is critical that a vibrant and successful country has a breadth and depth of chemistry expertise. That should mean that the best scientific talent is identified and nurtured to become our leading researchers. This should lead to reward and recognition for those brilliant scientists. You might imagine then that evidence that this has not happened and is still not happening would be something that you might want to keep quiet or else make damned certain you are actually addressing before confessing to. Sadly, the Royal Society of Chemistry (RSC) has once again announced to the UK that the discipline of chemistry continues to fail the nation. They announced their prizes and awards recently and here’s the thing: they give away almost £200K every year in prizes.

 

If, back in 1980 (when the RSC was formed), you had suggested spending the prize funds in such a way that it would be 2017 before more than 20% of that money went to women, I hope that you would have been sent away with a flea in your ear to think again. And yet, here we are, it’s 2017 and for the first time the proportion of money going to women (among awards going to individuals) has just crept above 20%. You have to believe some strange things about the abilities of the genders to not view this as an admission of failure. As far as I can tell, since 1929 there has only been one female recipient of the Pedler award, none of the Perkin prize (since 2008) and none of the Robert Robinson award (since 1964). While I cannot quibble with the selection of the recipients of these prizes (I have enjoyed working with several of them), this is a damning indictment of the discipline. If the RSC can really think of nothing better to do with £200K every year than to keep on advertising how chemistry is failing the UK then I am deeply worried.

 

Back in 2014 when I first took notice of the list of prizes, I wrote an email to the RSC on the subject and received a vaguely reassuring response (both published in the RSC news magazine). I was sufficiently annoyed by the following year’s published list that I threw it away in disgust. I have kept the 2016 and 2017 versions and have analysed them along with the 2014 list. I am happy to make the spreadsheet available. It is interesting that female recipients receive a slightly higher proportion of the money than of the prizes, although I think this just represents the over-representation of men in all of the prizes and there are fewer prizes that receive £1K or less. I also acknowledge that I have assigned genders on visual appearance from the accompanying photographs and names. It is also true that gender is a more fluid property than has long been assumed. However. To use any of that as an excuse or distraction would be inappropriate.

 

I note that in the UK parliament session beginning in 2001, there were 118 female MPs (18%), which had dropped slightly from the previous parliament. This caused sufficient concern and embarrassment that the law was changed to permit positive steps to be taken to change the situation. This has seen a slow but steady increase to the current parliament, which has 32% of female MPs. I am afraid that unless chemists collectively take positive steps to change their situation that similar governmental intervention might be required. We are not living through a period of time that can indulge a comfortable club for the boys controlling a vital national resource.

 

Chemistry in the UK – too important to accept such a large gender imbalance

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