as a computational chemist I must say end-use might differ significantly from these screening studies, it is more of a statement on current computing capabilities and a little bit of science icing
They could likely simulate tons more, but there is no guarentee that they are; Actually synthesizable, actually hit the target, aren’t toxic.
So at some point the current computing capabilites fall shot. But not because we can’t throw more cpu hours at the problem, simply because we don’t have the computational tools to cross those bery important barriers available at all.
Using more CPU time in this would have helped a lot.
The good news is that once the library is prepared, it is quick to screen at more targets--and we make the pre-computed library available at zinc15.docking.org.
Interestingly, as the library grows a limiting factor is storing the library on disk. It is now ~20T. We've set up several mirrors around the world for groups that are actively using it. An interesting problem will be to see if preparing compounds for screening on the fly (e.g. with machine learning models) can overcome this limitation to keep up with library growth.
A big question for us is what will the return on investment in screening larger and larger libraries be? One of the take aways from this work is if docking has moderate enrichment, than screening larger libraries not only gives more hits but actually can increase the hit-rate for the top scoring compounds.