Enamine/Atomwise Multitargeting Hits - Nearest Neighbours

[edwintse]

@mattodd I've done some scifinder searching on the nearest neighbours to the Enamine and Atomwise hits that @AJLloyd105 presented over the last few meetings. The summary is below. AW codes have been added to the masterlist and the spreadsheet correlating the "Z" codes to the "AW" codes is here.

MurLigase Multitargeting chemdraw.zip MurLigase Multitargeting chemdraw 2.zip

[mattodd]

Great work @edwintse. Let's discuss in the next meeting on Tuesday, but I reckon some of these are no-brainers for purchase if we'd like to flesh out some SAR @eyermanncj

[edwintse]

@mattodd @loriferrins @eyermanncj @AJLloyd105 @LauraDS1 I've updated the figure above to include close neighbours of the hit competition compound. We've funds to purchase a number of these so we narrowed it down to those highlighted in blue

[mattodd]

Great, thanks @edwintse. Those in blue are available from Enamine (single supplier easier) quickly and are structurally similar to the original compounds, helping to bolster SAR a little. Also added in four compounds similar to the hit from SPR reported yesterday. If anyone had any suggestions, please say, particularly @eyermanncj re the analogs of the actives from the "Warwick Enamine" collection. If we purchase these, we will still have a little war chest for a smaller purchase based on the data we obtain.

@edwintse I think we're going for 5 mg of each? Meaning we could get them sent to UCL then send on 2 mg, keeping some for other future screens?

[edwintse]

Yes, 5 mg each is the plan

[mattodd]

@bendndi noted on Twitter a PAINS risk with some of our preferred structures

https://twitter.com/MrBenGP/status/1580623392767897600

"Be careful with those molecules, pretty sure those are known nuisance compounds / PAINS via indiscreet reactivity with cysteines (diverse cysteine attack at the electrophilic CH2 adjacent to the carbonyl, with the thiotriazole as leaving group). similar to the reactivity seen for compound 12 , fig 2 on this excellent PAINS summary: https://drughunter.com/resource/aics-and-pains-mechanisms-of-assay-interference/"

@edwintse and others, let's ruminate.

[bendndi]

Looking at @edwintse post https://github.com/opensourceantibiotics/murligase/issues/89#issue-1397848201 its not all of these that are problematic, but the ones with triazole / tetrazole thioethers are definitely problematic and I've seen these light up screens and SAR tables in the past thinking "wow, breakthrough!" but eventually we realized that they were just highly promiscuous reactive groups causing massive assay interference. Obviously you can validate this via GSH trapping experiments or decent counterscreen planning in the cascade. From chemical perspective you could just make sure you also bring in equivalent molecules where the thio-linked heterocycle isn't such a good leaving group e.g. 3-pyridines or phenyl...

[edwintse]

Thanks for the suggestions @bendndi. I've had a look for alternatives to the problem ones (orange box). @mattodd what do you think for purchasing?

MurLigase Multitargeting V2 chemdraw.zip

[mattodd]

Looks good @edwintse. So the changes are the some (not all, since who knows?) of the original, potentially problematic, compounds have been replaced with the mst similar compounds lacking some feature of the problematic motif, e.g. triazole to phenyl replacements etc. All good. I'd been hoping there might be some ether or methylene isosteres that we could go for instead, but no?

Are the DrugHunter crew on Tw/GH? We should invite them along here to contribute if they'd like to.

Thanks again for the advice @bendndi

[edwintse]

Yes, just changes for the 3 problematic ones with thioether-heterocycles. Couldn't find anything similar with methylenes or ether unfortunately.