Mediaboss Marketing

Chemical groups are defined by the spatial arrangement and bonding of multiple of atoms in space, but these atoms are proximate to each other. When chemical groups interact, e.g. through hydrogen bonding or -bond stacking, the strength of their repulsion or attraction may vary with their type, distance, and angle, but these are predominantly local effects. More complex bioactivity features may be described by considering neighboring groups that strengthen or attenuate a given interaction but, because even in these cases distant atoms rarely affect each other, the enforced locality of a DCNN is appropriate. Additionally, as with edge detectors in DCNNs for images, the applicability of a detector for e.g., hydrogen bonding or -bond stacking, is invariant across the receptive field. These local biochemical interaction detectors may then be hierarchically composed into more intricate features describing the complex and nonlinear phenomenon of molecular binding.

Now, I have no problem with the local bonding calculations that theyre talking about doing, although theyre subject to the usual disclaimers about the accuracy of the calculations. But the assumption that "distant atoms rarely affect each other" does not seem to me to be valid. Medicinal chemists are quite used to seeing changes in a structure-activity relationship when a reasonably distant atom is changed "You can get away with a methyl there as long as you dont have one over there". There are SARs that do work on the "greatest hits" principle, where you can independently mix-and-match various regions of the molecule, but the great majority of the projects Ive worked on havent gone that way, or not quite. And if Im interpreting that paragraph correctly, its explicitly aimed at the mix-and-match. Id say that the most common situation is the one where you can get away with independent changes within a given range, which can be a rather narrow one, and then all bets are off. And the only way to discover that youve gone outside those ranges is to go outside them.

As mentioned, AtomNet, to its credit, also brings in data about the binding target. But thats a tricky business, too. As is well known, binding sites accommodate ligands by adjusting their own shapes sometimes subtly, sometimes dramatically and this is one of the hardest things to account for in virtual screening techniques. Likewise, the ligands themselves can adopt a range of conformations in response to a binding event, which also adds to the computational burden. Im not at all sure how this software deals with these problems, particularly the protein mobility one, but if I come across more details, Ill update this post.

From what I can see, the AIM program is screening databases of commercial compounds and furnishing the applicants with the 72 best purchasable hits. The compounds will be given an LC/MS quality check diluted to an appropriate concentration, and plated out, which is a good service. "Custom-chosen", though, does not mean "custom-synthesized", as youd imagine (I dont think anyone will be taking that on for free). Theyre asking that people come to them, ideally, with targets that have an X-ray protein structure and an identified small-molecule binding site, which is fair enough.

I would very much like to know what the hit rates will be for these, and I suspect that AtomWise very much wants to know that, too, which is why theyre offering to do this for people. The awardees get some potentially interesting molecules to test, and the company gets a presumably diverse set of real-world examples to test their technology against. (I should note that they already have agreements with several academic groups, and one with Merck (NYSE:MRK), for an unnamed project). Personally, Ill be surprised if theres much of an enhancement for many of these, but I wish the company luck, and I think that their commitment to putting their software to the test is admirable.

Is it "artificial intelligence", though? Thats a topic I touched on in my talk last year in Manchester. I think that if you time-machined people from the 1950s into our present-day world and hit them with Google Maps (for example), theyd probably call that artificial intelligence. "Sure, thats intelligent, although for some reason you only seem to have taught it about roads". From that standpoint, AtomWise would also be called AI, but from a modern perspective, if thats AI then so are the rest of the modeling and docking programs. Ill put that one down to press release language, and hope that it doesnt become a big part of their pitch.

The part that annoys me more is the "72 potential medicines" line. Screening hits are potential medicines in the same way that AtomWise is a potential Amazon.com (NASDAQ:AMZN) sure, they all start out this way, but not many make it through to the end. People are confused enough about where drugs come from and what it takes to get them there; Im never happy to see more confusion being dumped in on top of what weve got.

Link:
Free Compounds, Chosen By Software - Seeking Alpha