Was the compound AZ5595 in PDB: 6x9n was received from AstraZeneca?

[Yuhang-CADD]

Dear all,

I have been synthesising AZ5595, the title compound from the original AZ paper Pyrazolopyrimidines Establish MurC as a Vulnerable Target in Pseudomonas aeruginosa and Escherichia coli. .

This compound has also been identified by @PeterHoranyi in PDB 6x9n and released by 02/SEP/2020.

However, the original paper did not have any crystal structure of how this compound was actually bound to the MurC protein. I have no idea if the compound obtained by following AZ paper's protocol was actually the structure in the PDB 6x9n crystal.

There might be a slight chance that the "OH" end can also get attached to the pyrimidine ring instead of the "NH2" (as is shown in the following picture):

Obviously, we will soon obtain MicroED data of this compound from Diamond and we will know how exactly it looks like.

_But still, _we would like to know if the PDB structure 6x9n achieved by @PeterHoranyi was actually using the AZ5595 from AstraZeneca.__ If so, then it proves that the compound generated by the AZ paper protocol actually had the structure in the PDB 6x9n. And there won't be any doubts about whether the O end or the N end attacked the pyrimidine core.

Please help! @eyermanncj @mattodd

Many thanks, Yuhang

[eyermanncj]

Yes, AZ5595 was given to SSGCID by AstraZeneca. Also I think the x-ray reolution of 2.25 is good enough to distinguish between the 'O-linked' vs 'N-linked' compound. @mattodd @Yuhang-CADD

[mattodd]

Great, thanks @eyermanncj - we'll be able to confirm soon enough that the compound @Yuhang-CADD has made is active. Yuhang has also been trying to prove which way round the addition has taken place with NMR. (I don't think Peter Horanyi is on Github).

[eyermanncj]

See the attached supplemnetal data for the AZ paper with the analytical data for Compound 10 (AZ5955) AZ murC supplemental.pdf

@mattodd @Yuhang-CADD

[mattodd]

Sure, we have that @eyermanncj. Obviously that sample was bioactive, but there's no Xstal structure. We just wanted to be sure that the compound that was used for the (much later) xstal structure (in the protein) was from the same source.

[eyermanncj]

I am not how I can be any clearer. The compound was sourced from AZ

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From: Mat Todd @.> Sent: Wednesday, January 19, 2022 6:32:09 PM To: opensourceantibiotics/murligase @.> Cc: Eyermann, Charles @.>; Mention @.> Subject: Re: [opensourceantibiotics/murligase] Was the compound AZ5595 in PDB: 6x9n was received from AstraZeneca? (Issue #64)

Sure, we have that @eyermanncjhttps://nam12.safelinks.protection.outlook.com/?url=https%3A%2F%2Fgithub.com%2Feyermanncj&data=04%7C01%7Cc.eyermann%40northeastern.edu%7C57c9cb3545824762052608d9dba3ea37%7Ca8eec281aaa34daeac9b9a398b9215e7%7C0%7C0%7C637782319353223876%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000&sdata=L4lDGfrGc6VKfAd2Fth70s8AJTwU0uYWXcrUFfkmnZs%3D&reserved=0. Obviously that sample was bioactive, but there's no Xstal structure. We just wanted to be sure that the compound that was used for the (much later) xstal structure (in the protein) was from the same source.

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[Yuhang-CADD]

Thanks for the help, Joe! I think it's all clear now! As long as we are sure the AZ5595 was made by the same protocol we are currently following, shipped to SSGCID for crystallography and thus obtained the PDB structure 6x9n, then there is no problem at all now. Additionally, we will crosscheck with MicroED experiment of this compound in the upcoming month anywya!