Academics can spend time and resources doing, and publishing, things that people in the industry already "know". This keeps the grants, the students, the invitations to speak rolling in. It also allows you to cite their work when proposing something. This is key for the FBHG community. There are many luminaries in the FBHG field, and we highlight their work here all the time. Sometimes, they work together as a supergroup. Sometimes, Cream is the result.
Brian Shoichet and Gregg Siegal/ZoBio have combined to work together. In this work, they propose to combine empirical screening (TINS and SPR) with in silico screening against AmpC (a well studied target). They ran a portion of the ZoBio 1281 fragment library against AmpC. They got a 3.2% active rate, 41 fragments bound. 6 of these were competitive in the active site against a known inhibitor. 35 of 41 NMR actives were studied by NMR; 19 could have Kds determined (0.4 to 5.8 mM). 13 fragments had weak, but uncharacterizable binding; 3 were true non-binders. That's a 90% confirmation rate. 34 of 35 were then tested in a biochemical assay. 9 fragments had Ki below 10 mM. Of the 25 with Ki > 10mM, one was found to bind to target by X-ray, but 25A from the active site. They then did an in silico screen with 300,000 fragments and tested 18 of the top ranked ones in a biochemical assay.
So, what did they find?
"The correspondence of the ZoBio inhibitor structures with the predicted docking poses was spotty. " and "There was better correspondence between the crystal structures of the docking-derived fragments and their predicted poses."
So, this isn't shocking, but it is good to know. This is also consistent with this comment. So, the take home from this paper is that in silico screening can help explore chemical space that the experimentally much smaller libraries miss. To that end, the authors then do a a virtual experiment to determine how big a fragment library you would need to cover the "biorelevant" fragment space [I'll save my ranting on this for some other forum]. Their answer is here [Link currently not working, so the answer is 32,000.]
Sorry didn't make it past the link to Cream in concert. Quite made my day.
As I ALWAYS say, if I can't be informational, I like to be entertaining.
What I really like about this paper is that it shows clearly how empirical and computational approaches can find different fragments. It's a nice example of not using one technique or another, but rather one technique and another.
I agree that academics sometimes publish what is already "known" by people in industry and I would love if people in industry contributed to avoid this by publishing more of their findings. It would help the field move forward faster and we could all focus on doing new research. Still, academics sometimes show that what is " known" in industry is not valid or based on incomplete theories. Although publishing is important for academics, being cited is probably more important. So the academics who really do useful work for industry would also be helped by more publications from people in industry who cite their papers. I think this is how we can better help each other when it comes to the topic of publications.
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