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Call for Open Source Antibiotics Fragment Contributions #13

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danaklug opened this issue Nov 12, 2019 · 7 comments
Open

Call for Open Source Antibiotics Fragment Contributions #13

danaklug opened this issue Nov 12, 2019 · 7 comments

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@danaklug
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@danaklug danaklug commented Nov 12, 2019

Background: To address the need for new antibiotics, we have taken a fragment-based approach to discover hits against the Mur family of ligases, a target class which has been validated as essential to bacterial survival. In addition, these enzymes are absent from eukaryotes. A fragment library has been screened against Mur E and MurD as a starting point for optimization of small molecules against these targets.

What we have: Fragment hits from an initial screen against MurE and MurD, performed at Diamond screening facility, and a platform to screen additional fragment libraries or follow-up compounds. Further information about MurD hits can be found here. Further information about MurE hits can be found here.
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What we need: Additional chemical matter for screening. The Diamond screening platform is high-throughput and we would ideally be able to take full advantage of this. Some hits are currently being actively pursued (further information here, here, and here); others are not.

Since we’re at the early stage of the project, we need not worry too much about the contributed fragments being highly similar to the existing fragments. This is not a medchem hit-to-lead campaign, and the screened fragments can be quite different from what we have to date, but should ideally be of a higher molecular weight (i.e. 300-500 Da). Although we’d prefer fragments for screening, we are also accepting donation of interesting or unusual starting materials that can be easily coupled with building blocks to create new fragments.

Any donated compounds can be shipped to UCL, where fragments will be plated and sent to Diamond. Details about amount of compound needed and how to ship can be found here. Our first shipment will be at the end of November with future shipments every 1-2 months depending on compound availability.

Open source model: As this is an open source drug discovery platform, all data, including synthesis and characterization of donated compounds, will be shared in the public domain and there will be no protected intellectual property (i.e., no patents). An introduction to open source projects can be found here.

@pschmidtke

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@pschmidtke pschmidtke commented Nov 12, 2019

Hi Dana,
can you give access to the (all) structures coming out of the Diamond screening?

@danaklug

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@danaklug danaklug commented Nov 12, 2019

Hi Peter,
All of the hits we currently have are detailed in the wiki pages linked above, and the initial dataset for all compounds tested in the original screen can be found in this spreadsheet. The plan for future screening sets is to openly share the structures of all compounds sent to Diamond and the screening results here on GitHub.

Hope that helps!

@MFernflower

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@MFernflower MFernflower commented Nov 16, 2019

@drc007 @danaklug While I cannot contribute anything physical - I had doodled down some non-narcotic but potentially antibiotic compounds related to a molecule I probably cannot name on GitHub - would you be interested in computationally screening them against your target list?

CN(C1CCC(CC1)=CCC1=CC=CC=C1)C1=CC=CC=C1
CCC(=O)N(C1CCC(CC1)=CCC1=CC=CC=C1)C1=CC=CC=C1
CCC(=O)N(C1CCC(CC1)=CCCC1=CC=CC=C1)C1=CC=CC=C1

@drc007

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@drc007 drc007 commented Nov 16, 2019

@MFernflower Can you put them on the issue related to the particular cluster you had in mind.

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@MFernflower MFernflower commented Nov 16, 2019

@drc007

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@drc007 drc007 commented Nov 25, 2019

@danaklug @mattodd The article on LinkedIn has now been viewed over 1500 times and has 20 likes. Let's hope we get plenty of contributions.

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