Evariste Technologies compounds

[abrennan5]

Hi all,

We’ve already caught up with @mattodd about this but will just give a quick intro for everybody else. Evariste Technologies is a start-up focusing on a probabilistic approach to drug discovery. Briefly, the platform we’ve built, Frobenius, takes an existing dataset and identifies the most promising starting point/s, then designs a bunch of new compounds and scores them according to the likelihood of achieving a set of pre-specified endpoints.

We were really interested in the recent publication detailing the open competition run by the OSM team and thought we’d have a crack at the problem ourselves. The compounds attached are the output generated by Frobenius when it’s presented with the series 4 data. More specifically, we’ve taken the two most promising starting points, applied the various compound designers and selected a subset of the highest scoring compounds (filtered by a medicinal chemist for synthetic feasibility etc). The number associated with each compound is the probability of it achieving a pIC50 of 8.

As we mentioned to Mat, we’re keen to get some of these synthesised and are able to contribute towards cost of synthesis. We’re also more than happy for anyone interested in these compounds to use them as inspiration for similar structures, if this is the case, we’d really appreciate being kept in the loop as we can very readily score the idea in Frobenius.

If anyone’s interested in knowing more about the modelling than the (very) brief overview I’ve given here we’re happy to discuss in detail.

Best wishes,
Alfie

https://www.evaristetechnologies.com
https://www.linkedin.com/in/alfie-brennan-746ba6b1

Series4_EVT_Suggestions.xlsx

Malaria suggestions pIC50 8 .pdf

[mattodd]

Hi @abrennan5 - this is very interesting, thanks for posting. It'd be really great to make some of these, yes.

Could someone please take a look and generate a pic of the molecules we can quickly post into an issue, just to help with digesting the ideas simply (I know there's a PDF, I'd just like a cdx. Alfie if you have one, you can drag it here, but you may have to zip it up for Github to accept it).

I'm intrigued by the meta-subst rings in the northeast, which is something we played with a bit in @maratsydney 's work, but have not explored a lot. The accessibility of those will depend on availability of materials, I suspect.

For EVT-004 there's a CF3 there. I thought we'd done that?

Also of interest is the EVT-007, EVT-008, EVT-009. Didn't we take that N away (in EVT-009) already? Replacement with C-F and C-Cl is something we've not done.

[abrennan5]

Hi Mat,

Compressed cdx below. Each compound designer should drop suggestions that are already in the dataset but if any of these have cropped up before let me know and we can fix that.

Malaria suggestions pIC50 8 .zip

[edwintse]

I've updated the original post with the structures of the suggestions. Just some quick comments:

For EVT-004 there's a CF3 there. I thought we'd done that?
We have 1 compound with an OCF3 group as in EVT-004 but it has an amide on the LHS (MMV675963/OSM-S-271/TM 55-1).

Didn't we take that N away (in EVT-009) already?
Yes, we have 4 compounds with X = H instead of that N atom and a 4-CN on the RHS (from Patrick Thomson's work). Examples include both ether and amide linkers on the LHS but all are inactive.

I'm not sure if the synthetic accessibility of the benzylic OCHF2 group has changed but that was one of the things that we weren't able to remake from the inherited compounds. If we can't find a way to make that side-chain then all the compounds based on Starting Point 2 may not be accessible.

I'll have a look at whether the aldehydes needed for the different cores are available in the meantime and update later.

[abrennan5]

Great to meet you Edwin, thanks for uploading the image. Re the compounds containing the benzylic OCF2H, the OCH3 analogue was also one of the top ranked hits, see below for a set of suggestions from that starting point. Perhaps unsurprisingly, the model scores modifications of the methoxy group relatively highly as it views changes here as likely to increase potency. There were a significant number of designs in this region, all with around the same 4 - 7% chance of having pIC50 > 8. I selected the smaller changes to avoid having too much of an impact on solubility and logD. I've also (hopefully) fixed the filtering such that there shouldn't be any compounds already present in the dataset included here but please let me know if that isn't the case.

Let me know your thoughts around this set of molecules as well as just replacing the OCF2H with OCH3 in EVT-011/021.

OMe_suggestions.zip

[abrennan5]

Hi @mattodd and @edwintse,

I hope you're both well. Just wanted to follow up with our most recent work here, we're actually planning to publish the process of generating these ideas in a blog post at some point soon but I wanted to get them uploaded here first as it builds on so much of your hard work. You'll note the compounds suggested here are slightly different to those above. There are a couple of reasons for this; most importantly, instead of just optimising for improved potency, we asked the model to also aim for molecules with improved solubility and logD in the range of 0 - 4 (essentially 1 - 3 + prediction error). We have also used an updated version of our platform which predicts our error more accurately.

Finally, when selecting compounds we used a 'pessimistic design' algorithm which picks molecules for synthesis predicated on the failure of all the preceding molecules. This filters our list of 30 designs (based on three different starting points) down to 10. You'll note that in the PDF there are two predicted potency values, black is independent of the result for the earlier molecules, red is presuming that the preceding molecules failed to hit the desired endpoint (pIC50 > 8).

None of these feature the troublesome benzylic OCF2 due to the prioritisation of molecules which were predicted to be more soluble.

Happy to field any questions and share a wider selection of designs if that would be helpful.

Best wishes,
Alfie
compound_picker_suggestions.pdf
compound_picker_suggestions.zip

[edwintse]

Hi @abrennan5, I've finally had a look into potential synthesis of these compounds and it doesn't look like we'll be able to make any from your last post. I think the main issue is with the difluorophenyl ring - these substrates are typically more expensive to get a hold of compared to phenyl ring analogues, and this is especially the case when there are additional substituents on the ring. Just based on gut feeling, the compounds in your original post from Starting Point 1 are also less desirable as changes to the NE portion tend to decrease potency. I'm starting to think that the Starting Point 1 compound isn't the most ideal in terms of synthesising analogues. Any chance you'd be able to redesign some new compounds with this in mind?

[abrennan5]

Hi @edwintse, thanks for taking the time to review the molecules and potential routes, we really appreciate your input here. We can absolutely go from a different starting point, I'll remove both fluorines from that ring and see where we end up - most of the suggestions will design something back in in those positions, but the overall complexity should be lower.

I'll also look at building a virtual library using the published route, this sort of forward synthesis is something we're introducing more and more often on our projects. We can also take into account cost when doing this (very much a beta version of this feature at the minute and it is highly dependent on where the building block comes from).

I'll get something back to you later this week.

[abrennan5]

Hi @edwintse,

I ran the modelling again and selected some starting points which should (hopefully) be somewhat easier/cheaper to access. The two most promising analogues without any of the complex/expensive SMs discussed previously were:

• indole in the NE position and the phenyl ring with the pendant ethyl alcohol in the NW
• 4-chlorophenyl in the NE position and the simple benzylethyl ether in the NW.

I applied our design algorithms but I also built virtual libraries using in stock alcohols and aldehydes available from Enamine so at least some of the compounds attached should be easy to plug into the existing route. The building block price filter is still work in progress so I wasn't able to apply it here.

The modelling was the same as the previous post so the designs have been biased for improved solubility and then selected based on predicted potency. Changes to the NE portion still crop up and I suspect this is the case because the modelling views regions of steep SAR as relatively promising for finding highly potent molecules. The reason for this is that they might well be rubbish, but they could also be great if they pick up the right interactions close to the surface of the protein. There are a few anilines present which I would normally filter out, but in this case I chose to leave them in as they are also likely to be easy to make.

Happy to hear your thoughts on these, have a great weekend!
Alfie
new_starting_points.zip

[edwintse]

Hi @abrennan5, thanks for the new suggestions! We might have a go at making the higher scoring ones like the cyclic urea (0.07). Interesting that the 0.14 compound is predicted to be active. We've made the same compound but with the NH2CH2 at the 3-position and it ended up being inactive.

[abrennan5]

@edwintse Glad to hear a few of these might make a target list! I initially couldn't find the molecule you mention so I've had a look and realised that there were a small number (about 25) that had a potency value in the Dundee column but not in the collated 'PfaI EC50 uMol (Mean)' column we'd been using.

I've updated the modelling and the indole predictions are broadly similar with slightly (2-fold) lower success estimates. The drop off is broadly consistent with the other suggestions, with the exception of the 0.14 compound, which is now 0.03 and probably better reflects your understanding of the SAR. No other starting points jump up the list, most of the missing data was for inactive molecules.

Hope that helps clear things up!