Methionine Aminopeptidase as a possible target ?

[Giada-chem]

Metal-mediated inhibition of Escherichia coli methionine aminopeptidase: structure-activity relationships and development of a novel scoring function for metal-ligand interactions. From this paper emerges that Thiabendazole has a similar structure to our compounds ( two piridyl moieties): this drug chelates the cobalt ions present in methionine aminopeptidase in E coli and human.

Interaction within E. coli****

Schiffmann, R., Neugebauer, A., & Klein, C. D. (2006). Metal-mediated inhibition of Escherichia coli methionine aminopeptidase: structure-activity relationships and development of a novel scoring function for metal-ligand interactions. Journal of medicinal chemistry, 49(2), 511–522. https://doi.org/10.1021/jm050476z

Interaction within Humans****

Zhang, F., Bhat, S., Gabelli, S. B., Chen, X., Miller, M. S., Nacev, B. A., Cheng, Y. L., Meyers, D. J., Tenney, K., Shim, J. S., Crews, P., Amzel, L. M., Ma, D., & Liu, J. O. (2013). Pyridinylquinazolines selectively inhibit human methionine aminopeptidase-1 in cells. Journal of medicinal chemistry, 56(10), 3996–4016. https://doi.org/10.1021/jm400227z

Then, I got the christal structure of S. aureus met. aminopep in PDB (1QXY) with other chelating inhibitors and I docked this target with compound 00982.

Docking results :

• met. aminopep with the chelator found in PDB ( spheres are cobalt ions)

• met. aminopep with compound 00982:

It seems that it is too bulky to interact with the ions.. What do you think ?

• Here 2D view:

[MFernflower]

STP1 is another possible candidate target - PDB of that is known 5F1M @mattodd @Giada-chem

[MFernflower]

So far our possible target list is:

MQO1 STP1 MAP1

@mattodd @Giada-chem

[Giada-chem]

Hi! I tested computationally STP1 , I docked this target with compound 00892 and it seems not to work.

Did you test these targets?

Best, Giada

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Da: MFernflower @.> Inviato: lunedì 15 marzo 2021 16:08 A: opensourceantibiotics/Series-2-Diarylimidazoles @.> Cc: Sabatino, Giada @.>; Mention @.> Oggetto: Re: [opensourceantibiotics/Series-2-Diarylimidazoles] Methionine Aminopeptidase as a possible target ? (#58)

So far our possible target list is:

MQO1 STP1 MAP1

@mattoddhttps://github.com/mattodd @Giada-chemhttps://github.com/Giada-chem

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[MFernflower]

No- I do not have access to docking software

[Giada-chem]

ok, MAP is methionine amino-peptidase?

because I am actually working on it

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Da: MFernflower @.> Inviato: lunedì 15 marzo 2021 16:46 A: opensourceantibiotics/Series-2-Diarylimidazoles @.> Cc: Sabatino, Giada @.>; Mention @.> Oggetto: Re: [opensourceantibiotics/Series-2-Diarylimidazoles] Methionine Aminopeptidase as a possible target ? (#58)

No- I do not have access to docking software

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[MFernflower]

@Giada-chem MAP1 is indeed

https://swissmodel.expasy.org/repository/uniprot/A0A0H3K984?csm=3E42E623286B537B

(interesting to note the inhibitor they crystalized this enzyme with has a 2-pyridyl motif) @mattodd

[MFernflower]

@Giada-chem also see this: https://www.rcsb.org/structure/1QXY