[pizza]

Someone with PZM21 knowledge! Intriguing! Would there be any point to using low-granularity approximations of 'disjoint-class-ish' molecular backbones and building upon best candidates, doing some kind of low-res hill-climbing in effect, before increasing granularity with the best ones?

Granularity might be some kind of "well we need some kind of phenol or phenol-derived ring here, why not just replace that with some sort of representation of 'phenol-like-ring-here'" or something to that effect.

Also, about PZM21 -- will it ever experience the same fate of U47700, or the likes of the orphaned opioids resurfacing from their watery graves?

[momeara]

In theory I think you are right--there should be a tower of representations from low-res/fast to high-res/slow. Though in practice it has been hard to make multi-resolution modeling work together. For example for proteins, where the backbone is much more regular than small molecules Rosetta has "centroid mode" and "full atom mode". There is also MM/QM models where just the active site is modeled with higher level of theory representation.

For virtual screening it is possible to speed things up by say not taking into account receptor flexibility or ignoring explicit interactions with water.

As for lower resolution representations of small molecules, there is ROCS[1] and friends which represents small molecules with a set of gaussians.

One of challenges with low-resolution representations is that the aims of virtual screening is often to find novel backbones that may interact with the protein. So any low-resolution representation should mix different backbones into the same cluster, but finding such a representation is difficult, given the diversity of small molecules.

As for U47700, finding the mechanism of action for drugs that treat complex processes like pain is quite difficult. Also small molecules often interact with numerous targets so deconstructing how it works is non trivial. Part of the motivation for PZM21 is to try to separate out the downstream effects of hitting the mu-opioid receptor as a "biased" ligand. I think PZM21 with its new scaffold will help disentangle the effects of classical opioids.

[1] https://www.eyesopen.com/rocs

[pizza]

Any concerns that PZM21 will be an even 'better' designer drug than U47700, O-DSMT, MPP, hell even heroin? Especially due to the adversarial nature of clandestine chemists and their respective nations' law enforcement agencies. Then again, taking a peek at PZM21's shape, good luck out there to all the non-sigma aldrich tier chemists who want to make their own, lol.