Open Source Antibiotics Series 2, 6 Nov 2020

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From YouTube: Open Source Antibiotics Science Update Nov 6 2020

Description

Weekly open project meeting for Open Source Antibiotics Series 2.
Full Project: https://github.com/opensourceantibiotics/Series-2-Diarylimidazoles
Relevant GitHub Issue: https://github.com/opensourceantibiotics/Series-2-Diarylimidazoles/issues/38
On the call: Professor Matthew Todd, Dr Dana Klug, Dr Edwin Tse, Dr Chris Swain (Cambridge MedChem Consulting), Anthony Sama,

A

Okay, welcome to open source antibiotics series 2 meeting on friday november, the 6th um thanks for taking the meeting last time and um and the recording is now on on youtube. So that's all uh um I haven't had a chance to look at this week, so it would be very good if we could just talk a little bit about what was discussed last time into the compound design, so just to um very, very briefly bring people up to speed.

A

um So the uh issue for this meeting is up there and we received a bunch of stuff on potency essays last time. You know two weeks ago and um and the last meeting, which I couldn't be out. Unfortunately, you guys were talking about what to you know, design and make for the next round, based on these new data, which were pretty interesting.

A

um So I guess you guys spoke about that a little bit last time and we can talk about what what you were thinking about and then we can make some decisions. Does that sound good.

B

Yeah fine with me.

A

Okay, did you guys have a slide or something of decisions or anything from last time?

A

A

All right do you wanna, walk through walker.

C

Yeah, so this is just compiling all the compounds from that issue. um So yeah the ones on the left are most straightforward. It's just you know the same reactions um so we've so I've made the parachloro just.

A

One sorry one sec, the so the rationale behind those is arising from this parabolic.

C

A

Yeah, which had the paramethyl, which was active right and um okay, fine and so you're. Obviously, most of these are exploring that position with the same chemistry, which sounds good.

C

A

Yeah, okay and we didn't yeah- I mean just based on what we already knew about that. So we we've got this meta cyanide cyanogroup, which is inactive, and we've got this para oca cf3 group, which is kind of middlingly active. So I guess we just want to explore the power position.

A

I guess yeah um I mean.

B

I think I think I think you have to be a bit careful about the log p of some of those compounds right.

A

Yeah we yeah. We need to have that cracked yeah.

D

I uh did track a couple of them: the top three or ones I designed they're a little bit better than the pair of than the hollow one, uh but a couple on the bottom are pretty greasy, but yeah yeah. That's that the creeping log is a problem in every campaign. I think.

A

Yeah, okay, sorry ed! You want to just um sorry just carrying what you were saying.

C

Oh uh and then yeah the rest of them are, uh I guess, slight modifications on the main structure, um so I think chris suggested this methylene dioxy bridged with the amine um and then there's uh putting the paramethyl channel on the five six core, um which we can do um these two in the bottom, where we're removing one of the nitrogens. I think that's nice, but I think it'd be a lot harder to make.

B

I I also think the one you have in the bottom middle will exist as a pyrrole, so it'll be the nh.

C

Yeah um so yeah not sure about those um these ones. uh I guess we can make. um I think we've we've started to make this uh methoxy core um and then this other one with the uh replacement heterocycle.

B

So the thiozole is a bioisoteric replacement for a pyridine. That's great.

B

I think the one the one on the what was it um bottom row left hand side where you remove the nitrogen imidazole. It's just following on the idea of trying to explore whether we do need a bidentate ligand. There.

A

B

So I think it's a it's a it's a it's a compound for providing information rather than increasing.

A

Potency it's interesting because then the one on the right in the middle bottom, the one you're just saying that would exist as the peril um that also, if it had an nh, would not be coordinating.

B

That's correct, yes,.

A

Quite neat, actually, as a tester.

B

So it's really a question which is easier to make.

A

uh Yeah yeah synthetic difficulty, yeah.

C

uh I had a quick look at trying to get those cores and I've not really found anything reasonable. Yet.

B

Okay, could you do? Did you try and look to ones where you have the benzo ring on there? Instead of the uh saturated ring.

C

uh Yeah, I think I did, and it was okay, similarly difficult.

B

A

Yeah: what's the rationale sorry for the methoxy on the fused core where's? That was that, from a result,.

E

A

E

Right here, there's a match pair set in the dndi compounds, where one has the methoxy and one does it on the core and the methoxy one is more potent. So I think I'd like to see if that trend holds, because I think that that's interesting.

A

Yeah good: what about? um Is there a value in uh just looking at what we know here, so we saw that the param paramethyl in the original set is the one with the activity. um Is there rationale in moving that to the meta just to explore that space?

A

If it's simple, to make just moving it around, because we're we're putting a lot on the power being useful here.

B

I think, if you're going to, I think that sort of exploration is always worthwhile doing. But you know the classical topless tree would start off with a chloro compound.

A

B

And just move it around the ring.

A

Okay, so I mean if we can explore the isomers yeah. That will be neat if that's synthetically, straightforward yeah.

A

All right great any um potential. uh What's the word bottlenecks here synthetically I mean in terms of precursors and stuff, or is it it's all derived from the same kind of chemistry right on the left, in particular,.

A

Yeah just bronic acids- I guess yeah okay and have you chosen them in part? Because of that I mean because they're available.

C

D

Top three are available: top four are available, the more lipophilic ones are a bit difficult to come by, but you could probably make the one towards the bottom out of like para, bromo cumin, which I believe is available.

A

Okay, all right good sounds good. To me, I mean that's all the most relevant things. Isn't it yeah the sf? The sf5 is just me playing around.

E

uh Yeah, in my opinion, probably those bottom three are lower priority.

D

Yeah they're, probably the lowest priority of them. Okay, although you could yeah, you could probably I mean, although if you do, although I guess we could kind of meet in the middle and say if you have para cf3, boronic acid, that would be something to see if lipophilicity has something to do with the way it works, but I'm not exactly sure because that's not going to be very soluble. Is it.

A

I think in each case, if you can dump this slide on the get obviously be very useful, with the with the um log p slash log these put in there.

A

That would be very helpful um also if we start mov, if we start changing the core a little bit like we have that, on the right hand, side just another quick check on scifinder for anything that we may be hopping over to sources of compounds or literature that we may have missed, because we've been focusing on the left hand, side, not sure there'll be anything there, but with the thiazole, for example, just check that we're not hitting something which has already been made in a different paper or project.

B

I think that if we could explore whether we do need that bidentate ligand and then if that is important, you can think of a lot of things that you would replace the pyridine with which could also coordinate and would have very different chemistry.

A

Yeah yeah, okay, I agree yeah, there's a good one for that too.

A

um The so just on that point about toxicity, because that is absolutely going to be important here too. Isn't it um yeah the so sorry dana? Do you have any any update on the on the testing for the fox.

E

Yes, um it hasn't been started, so ed most recently has been in touch with alex because she wanted me today.

C

Yeah yeah, um so she I'm gonna, meet her after this meeting uh and give her the eight compounds. Oh.

A

Awesome! Okay, great great, so.

C

Yeah, I think it's like a three-week turnaround or something okay,.

A

Okay: um okay, that's great! Thank you thanks for taking care of it, um and obviously those are crucial. The the thing that I'm thinking about with the potency data. um This may be naive, but they I mean. Essentially all of these compounds have similar uh ability to kill metal and yet tinkering around with a remote site changes the potency.

A

So it would seem to me that would argue against a generic potency generic toxicity mechanism, but you know the proof's in the pudding right, but yeah well,.

D

The moa studies, then then we can uh get people in to do docking once we know.

A

Yeah, but what I mean is that you know I guess I was. I would expect many of these to be. Oh, I would expect yeah. I would.

D

Expect if it was like a pains to uh just completely plow through all the cells and leave nothing behind, um but I'm not sure this is it's a very unusual core, the only thing that even remotely looks like it or the the insomnia drugs, the z drugs.

D

The only thing that remotely even looks like that.

B

I think what you're saying matt is absolutely correct if it's a generic toxicity, but of course it could still be a specific mechanism for toxicity, which has its own sar yeah.

B

We just need the data.

A

Yeah yeah, okay, great, it was good that that's happening.

D

Is there any update on the moa studies.

A

Oh yeah, I don't think so right they're supposed to have been done, but we haven't checked in.

E

Yeah I said I would follow up last time and I have not done that, so I will I'll follow up with that this week.

A

A

Okay, so those are the most important things. I guess um and we are on top of them. That's good, so um danny you're non-chemistry this week, but I guess ed you're, still around holding up the fort and decorating the lab.

A

um All right, so just going back if you wanted to oh you've, got a chemistry update.

E

A few reactions so, but these are all in my hood just during at room temperature at this point, um but it was just looking at whether we could make the methoxy core and then also with a chloro there, which we had sort of talked about last week too, um by the same method that we're making you know our other cores. So I set those up. I need to deal with them when I come back um and then ed suggested.

E

Looking at the um osm, you know snar protocol to put the um the amine linkers onto this bromine core that we already have so I've set that up too. um If that doesn't work, I can try. You know, there's several things. I can try, maybe a buck wallet or something like that. So.

D

Maybe microwave.

E

B

If it's, uh if there is a potential for a bidentate ligand there, if you were to put in something like zinc, would that coordinate to the nitrogens and make it uh more receptive to a nucleophile.

A

A

Yeah, I reckon that's a good idea worth a shot.

E

Yeah, okay, yep, that's another one that I need to check. Also so I'll. Let you guys know when I get back in the lab.

A

If you want um advice on the book file, heartbreak then just get in touch with marek, because he's been all over this with uh examples of molecules that he means.

A

He's got all the conditions covered, nice.

D

I would have tried a buckwheat heart rate, but that's gonna be uh annoying, isn't it.

A

For the top depends, it's you know, yeah, it's it's a mixed report in the literature about the influence of the pyridine and stuff all right. Great though, and ed you you're in the bottom of the slide, you're muted. I think.

C

uh Yeah so the left three compounds I made last week, um so there's a done and then these other two with the chloro ones. I did this week um so yeah there's the parachloro one that yeah suggested um and then so we were thinking as well of putting the benzofuran on the core, but with the amine spacer.

C

um So I found a prep for this, but it uses this ligand, which I have to make, which is pretty easy, but uh yeah that should get us that and then we can put that on the core.

A

Okay and then we want to see if that is um those two things are potent before we do any more of those yeah, because it's a significant, you know three-dimensional change.

B

Can you use that ligand and conditions for reacting the bromine with uh say an aniline as well.

C

E

Yeah we can't look at. We can look at that. I think yeah. I think we should be able to make them these amine spacer compounds using this core that we already have it's just a question of how exactly.

B

A

That is a neat ligand. The mnfo I'm not familiar with.

F

It almost looks like that uh compound. That's in glow sticks.

F

Like something it's a dioxal, it's like an oxalite.

A

That's neat all right, great, very nice cool and uh with the ten percent deal with the chlorine, you don't really care because you're gonna.

C

A

Okay, all right, wonderful, good stuff, um so just um anything else that's left here I mean you know what we talked about the most important things. um The everything else is still there. I'm continually tubing away at everything else. That's going on here. um The moa stuff is, I think, maybe the the thing which we've got a pretty good expectation, getting something back on pretty soon um the other stuff. Here I mean then you've got so much time now to make community updates.

A

So something you know 30 seconds 29, maybe.

A

And uh the only thing that there was a I mentioned, the market contributions yeah, so how people might be able to um contribute uh molecules, and I think from them from memory were we talking about actual samples chris? Is that what you're getting is.

B

Correct yes, yeah right, I mean these types of structures. It would not be surprising if people don't have samples of this sort of thing in their sample collections.

A

E

Yeah well, I sort of made up um like a draft spreadsheet. I was thinking if we you know if we wanted to set it up so that people could download it. It has all the shipping information on it and it has you know all the information that we would need. So we I was thinking we could just like, ask people to download that and fill it out. If they wanted to donate compounds, it would all be sort of uniform and you know easy to do.

E

Hopefully, that's neat yeah yeah sounds great, the question of where to put it and how to publicize it. I guess.

A

There are two two things I mean: are we saying that we would? Are we saying that we would be happy with molecules that humans are saying are related to the molecules we're interested in? Are we happy enough with that? It's an intuition thing or do we want to say only if they're like 10 in the 90 plus percent or something.

B

I think if people are willing to donate them, I'd test them. If you can.

A

And we need some basic level of agreement about what we're allowed to do, which exists already in the sgc probes program. So we can basically point to that page and say: if you agree to this, then you can submit compounds yeah. um So we can include that link on it too. Do you danny? Do you want to um put if you've got a spreadsheet? That sounds really good.

A

If you could just start a new isu and dump it there, okay, we can come up with some text that we agree to about what it exactly is we're asking of people yeah.

F

And I can put a.

A

Link to the to the agreement, the sgc has that clarifies terms.

E

Yeah yeah, especially in the license or the agreement, were you know in the same place and easy to find, and that would be good.

A

Yeah yeah just so, we can get everything together, so we're clear what we're saying what we're going to send out and then we can do that um and and to be clear about what it is that we're going to as well. So you know if people send a couple of milligrams and if we use a small amount of it. If we're left with the compound, we just need to clarify whether we're allowed to do anything with that or whether we have a requirement to keep it.

A

You know those kind of little niggly things, um it's as well to be really clear about all that before submit things.

A

Yeah ownership essentially um but yeah. I agree that would be really really nice. Okay, I mean, I think that was everything else that needs to be talked about now. Everything else is kind of just sitting around bubbling the background um I mean just taking a step back for the big picture stuff.

A

The purpose of this project, which is not meant to be infinite in length and expense, is to try and get us into a position where we are looking good to apply for for follow-up funding um to to for the project and what that means is clarification on sorry, improvement of the molecules um to the point where they're looking interesting.

A

uh Ideally, some information about moa and some evidence that there is community interest in doing this project. So the contributions to molecules from the outside from you know, via ben and dndi, was really important. The the idea of extra donations of compounds again would really help that um that, by virtue of being open, you know people are happy to submit things, um and I mean the other data. We just have to try our best, but we do we.

A

We do need to sort of put a little bit of a ring around it to make sure that we we don't pour in enormous resources and try and finish everything, because this project is meant to be advancing this to a point where we can apply for funding. If you see what I mean, ideally, we publish something obviously um as a complete piece of work, so um the chemistry we're doing, I think, is going for that.

A

Absolutely we're trying to zoom in on the active compounds and the moa is crucial, so I think we're doing all the right things um just just be aware that, ideally, what we go for is a is a is a sort of publication in the short term and a clarification of what needs to be done. If we had some more money.

B

Is there anything else we could do for a mechanism of action then.

A

um um Well, there is, if we um sent in active and inactive for a kinase panel or something we could get that done. um I think our unc friends would do that um for us, so they they'd send that to in one of the um uh you know, kind of panels that they run every now and again, when they've got a spare row kind of thing, yeah.

D

A

Could definitely ask for that, in fact,.

D

What about the um seeing the metal binding potential of these.

A

Just as a general precaution, so we I mean absolutely I mean you know. I think, there's no doubt that if we do that, nmr experiment and we add in a metal we're going to see something because it's it's coordinating.

A

I just, I guess, I'm not quite sure what we need into that or whether what we need to be doing is trying to hide trying to identify any any um any known enzymes which which are known to bind motifs like this in an active site. Let's say I said you know a metalloenzyme which is susceptible to things like this. Is there any way of zooming in on that.

A

Or is there any target which seems likely, based on similarity of structures, of these molecules that we're working on with other things that are known.

A

I I don't know.

A

um Because, of course, you know what you really want to do is is some experimental thing which maybe flags something up as a potential target. Ideally uh I don't know yeah, it's a it's a really good point. I think I mean you know what. If the yeah the unc stuff comes back blank or uncertain or unclear, it would be nice to have a plan b, yeah yeah kinase panel. Being one obvious thing, um any other evaluations we could do.

E

Have we have, do you guys have any experiment, experience with setsa assays.

A

E

Cellular thermal shifts.

A

Yeah, those are the ones that I think that lee graves can also do.

E

Okay, cool um because I know that, like the rsc and other organizations have these like smaller, you know, dollar awards and things that you can apply for which would maybe fund you know one or two experiments like that.

E

um If, if it's not under the purview of the farm alliance, grant hmm yeah.

A

Right if you're thinking about available screens um beyond, like co-ad and beyond, like um arrangements on on kinase panels and stuff, like that, what else can we, you know the nci used to have a cancer cell line, a bunch of cancer lines right that you could submit compounds to which we could also have a go out things things that are available where we can ship compounds and have them done?

A

um What are we missing something there? I don't know chris, I'm out of date with the with the nci panels,.

B

Yeah, I I don't know about free ones, but I mean there are commercial ones where you can submit a compound and they will put it through a vast number of assays, but they you pay for them.

A

What's you know to the nearest thousand, what what are you talking about.

B

uh Probably something like three to five k: yeah, the another sort of uh possibility is you you could set up a competition for uh people for insilico prediction of mode of action or likely target.

A

Yeah, that's the kind of thing I was thinking. um I mean we had a. We had a lot of interest in that on open source malaria series three when tom was asking about that people really just went for it. Yeah.

A

And uh and you never.

F

Know what's going.

A

To come up sure we could, we could frame it as that, and I guess we have. We have maybe enough data now for that to be useful lots of inaudible several actives.

B

A

That's not bad um so.

B

We're not asking for them to compound. What we want them to do is predict the target.

A

Yeah, absolutely I mean I don't know if it perhaps we should wait until we've got the talks data so that we know if we're.

B

Yeah, I think, that's fair yeah. I think that's fair comment. I mean, I think you wouldn't want to set up all the program and then find out. All compounds are toxic.

A

Yeah, okay, but it's sensible to try that um and I and I think to some extent, um lee graves experiments are uh biased towards kinases already. So I think the targets they're looking at are mostly, though so, we'll wait and see what comes up there, and then we can think about maybe doing that more generally, but I think it's a great point yeah.

A

It is ultimately something we need clarification on. Yeah, okay, I think that's everything. Thank you. That's been really useful. When is the eta on the tax data about three weeks? I guess three from now all right. I think so something on that. uh Let's see how it goes, we'll we'll keep everyone posted. I guess yeah any updates on that. Just pass them right along all right. Thank you. Everybody, nice, to see you and see you again soon.

B

All right, bye.