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.]