Thanks for putting more care into the answer than I did the question. 😊 I don’t have a problem here, was just riffing on the conversation. I suspected the way to do this was use a latent representation and since Jon is talking about conformations, perhaps he already has it.
From: Friam <friam-boun...@redfish.com> On Behalf Of Roger Critchlow Sent: Tuesday, October 12, 2021 10:17 PM To: The Friday Morning Applied Complexity Coffee Group <friam@redfish.com> Subject: Re: [FRIAM] Schwill Rock? As long as you stick to basic CNO type chemistry, you can probably figure out a valid SMILES generator pretty quickly. But it might be easier to work in the explicit molecule graph instead and just use SMILES as a content name string. The things that might go wrong after the SMILES input parses correctly are 1) a ring that's strained because it's too tight a turn, 2) steric hindrance between bulky sidechains occupying the same space, and 3) something that no one has any idea how to make. You could probably notice 1) and 2) if you track the average energy per bond. The benzodiazepines are a classic example of structuring the search around a core framework and substituting side chains onto the core. That's the way the chemists do it in the wetlab. OpenEyes (https://www.eyesopen.com/) is running some online events this month that might be interesting. -- rec -- On Tue, Oct 12, 2021 at 5:44 PM Marcus Daniels <mar...@snoutfarm.com<mailto:mar...@snoutfarm.com>> wrote: A search algorithm that, say, proposes a prefix or a suffix to a SMILES string would need to have a way to autocomplete candidates before it could use these descriptors to guide an optimization because the parsing step is non-trivial, never mind the sanitization step (mentioned on that web page). I will deflect blame on Jon for changing the topic from music to chemicals, but presumably with enough debate their aesthetic preferences in music could be formalized in theory or some rule-based way, as is manifest here. From: Friam <friam-boun...@redfish.com<mailto:friam-boun...@redfish.com>> On Behalf Of Roger Critchlow Sent: Tuesday, October 12, 2021 2:10 PM To: The Friday Morning Applied Complexity Coffee Group <friam@redfish.com<mailto:friam@redfish.com>> Subject: Re: [FRIAM] Schwill Rock? Hmm, when I was in the drug discovery canal, the "descriptors" that you could calculate from a SMILES string were legion. Here's the list for RDKIT, https://www.rdkit.org/docs/GettingStartedInPython.html#list-of-available-descriptors. There are one bunch that depend entirely on the formula and molecular structure. Then there's a whole other bunch you can compute if you generate 3d structures for the molecules, possibly multiplied by the number of low energy structures the molecule can adopt. What kind of plausibility were you looking for? Does the SMILES string specify a real molecule? That's hard. There are syntax errors in SMILES, failures to close rings, valency errors, charge errors. But there are lots of syntactically valid SMILES that won't match any known molecule, either because they're impossible or as yet to be determined. The pharmas all have their own lists of molecules of interest, but those are proprietary. Looks like there are various online databases, none that I'm familiar with. If the SMILES parses, you can try generating a 2d depiction and a 3d structure. Those will throw exceptions if things get too weird. -- rec -- On Tue, Oct 12, 2021 at 3:22 PM Marcus Daniels <mar...@snoutfarm.com<mailto:mar...@snoutfarm.com>> wrote: I was playing with RDKIT the other day, and it wasn’t obvious how to get a scalar quantity of plausibility of a molecule. It seems a SMILES string is right or wrong, and then maybe there are some warnings that can be trapped. However, the benefits for search or fair sampling are different than the needs of correctness checks, which is deeper property. That isn’t quite a fit to the music example where aesthetic considerations are subjective. From: Friam <friam-boun...@redfish.com<mailto:friam-boun...@redfish.com>> On Behalf Of Jon Zingale Sent: Tuesday, October 12, 2021 12:11 PM To: friam@redfish.com<mailto:friam@redfish.com> Subject: Re: [FRIAM] Schwill Rock? "I mean from the perspective of aesthetics. Understanding why Pandora is messing it up means sampling the deep wells." Yes, but not more than one has to. This is why I am advocating for methods like a weighted ensemble. The working analogy for me comes from drug discovery. It doesn't make a lot of sense to probe the same old sites and the same old conformations. .-- .- -. - / .- -.-. - .. --- -. ..--.. / -.-. --- -. .--- ..- --. .- - . 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