Economics has sometimes been called the dismal science. Whoever coined that term would appear to be unfamiliar with the literature of virtual screening.
It all started with the Blue Team’s comparison of docking and scoring methods. The Red Team’s analysis came to different conclusions. In particular the Red Team’s favourite docking program didn’t appear to have performed as well in the hands of the Blue Team. The Red Team suggested that receptor preparation by the Blue Team may not have been optimal for the Red Team’s favourite docking program.
The Red Team soon discover that baiting an opponent is best done from a position of strength as the Blue Team’s response is swift and decisive. They re-run their analysis using the latest version of the Red Team’s favourite docking program and, while they note an improvement on their initial results with the software, this still falls well short of what had been claimed by the Red Team. They also get the developer of the Red Team’s favourite docking program to check things out and he is also unable to achieve the success of the Red Team. As one of Macbeth’s witches may have said, ‘By the pricking of my thumbs, something aromatic this way comes’.
The play is now deep in the Red Team’s half and their response under pressure is somewhat underwhelming. It turns out that the Red Team’s favourite software is now behaving more as it did in the hands of the Blue Team.
Now take a real close look the Red Team’s response. Note the order of the authors in the Red Team’s original paper and in the retraction of the results for their favourite docking program. Careless? Maybe not?
Don’t you just love it when it gets bitchy!
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15 comments:
Thanks for drawing my attention to this contentious thread of articles. Can you clarify whether you mean the href="http://dx.doi.org/10.1021/ci7003169" Blue Team's response or Red Team's?
Many thanks for spotting my careless error. Blue Team's response is now correctly linked.
Can you extract and publish some of the choicest juicy bits?- don't have access to these journals.
In response to anonymous #2, I'm sorry that I won't be publishing any extracts. Not much to comment on and the moral of this cautionary tale is that it is better to be checking your results before attacking than after being counter-attacked. If I can find what I'm looking for, the next Crapshoot will feature an article in journal that you may indeed have access to. It has a high impact factor and is quite well known. Stay tuned and thank you for reading The Great Molecular Crapshoot.
Blue Team is well-known for doing meticulous studies of docking. We had corresponded with them once.
i was just reading these papers a couple of days back. Another interesting paper is one in which the blue team compares the conformations of free ligand Vs ligands in the active site of proteins.
Ashutosh, Blue Team are formidable opposition which makes Red Team's frontal attack all the more surprising. I am reasonably familiar with Blue Team. Red Team for me are much more of an unknown quantity.
SKS, Blue Team's contribution to strain energies will certainly feature when I take a look this sometime. However I need to look at molecular interactions first so that's some time off.
All, there are some problems with that paper on strain energies by Blue Team that you are citing. But we can discuss them when it is noted. Suffice it to say right now that "Results obtained in such studies are method-dependent".
Strain energies are a real minefield and I would expect some problems with most publications on the topic. Generally docking tools don't deal with strain energy in a particularly convincing manner.
You are quite right, and many "dockers" think this is one of the biggest challenges and are trying to address it. The answer to "How much strain energy does a ligand have (or the maximum possible that it can have) when it is bound to a protein" is to my knowledge still out there.
To some extent it's like income and expenditure in the financial world. You pay strain energy and get back binding energy. The maximum strain energy compatible with binding is limited by the mamixmum binding energy for that ligand. If you can reduce strain energy while keeping everything else the same (we live in a ideal world for the purposes of this discussion), your net gains will be greater. A strained ligand should always be treated as an opportunity although, in my experience, stereoelectronic stain is not that common. I plan to take up ligand strain energies sometime in the spring.
And there you hit it right on the head; the real question still is, "How much binding energy can a protein have for a ligand?". That seems to be still the minefield of contention.
I'm familiar with all of these papers already, but I didn't realise you were talking about them when I read your post first. It would be really useful if you could name the paper and authors as well as providing the DOI. I actually came across your post a second time via a link to your blog post from the ACS web site (thanks to the DOI, Chemical Blogspace, and my Greasemonkey script).
We prefer to keep names of people and journals out of the text of the Crapshoot entirely. Doing it this way makes it much clearer that Crapshoot commentary is about specific articles in the published literature and not individuals, institutions or specific journals. Sorry not to be more accommodating but we hope you will understand.
Wait, wait, wait, I almost missed ashutosh's comment:
"How much binding energy can a protein have for a ligand?".
I admit I don't even understand the comment. Certainly "binding energy", no matter who defines it, refers to the complex versus the individual molecules. One can neither define nor distinguish whether it is affinity of the protein for the ligand, or visa versa. Nor, I would argue, is that even a meaningful question.
Or are you referring to something completely different, and I need to go drink some more?
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