tag:blogger.com,1999:blog-1136153439451224584.comments2024-03-18T02:52:17.621-07:00Practical FragmentsDr. Teddy Zhttp://www.blogger.com/profile/07288045760981372367noreply@blogger.comBlogger1466125tag:blogger.com,1999:blog-1136153439451224584.post-83078646632751471222024-03-18T02:52:17.621-07:002024-03-18T02:52:17.621-07:00Thanks for this write-up, Dan! Lovely to stay in t...Thanks for this write-up, Dan! Lovely to stay in touch with the topics covered at one of my favorite fragment meetings. Too bad I couldn't attend...<br /><br />Do you also intend to cover the reborn FBLD 2024 meeting coming Sept. in Boston?ARBhttps://www.blogger.com/profile/15121800178514123647noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-19772127837847618162024-01-22T11:54:10.702-08:002024-01-22T11:54:10.702-08:00I hope the point about dissolving compounds in 10%...I hope the point about dissolving compounds in 10% DMSO giving different results is not a surprise to too many people. I think there has been data for many decades that compound solubility does not scale linearly with DMSO concentration and so if you take a 10 mM DMSO solution of a compound and then dilute it 10-fold with water, there is a good chance the compound will precipitate out of solution whereas if you dilute it 1000-fold or 10,000-fold with water (or buffer), it may not. So when doing a dose-response of a small molecule dissolved in DMSO, I think a good practice is to make different dilutions in DMSO and then dilute these all into water/buffer as a final step and not try to make intermediate solutions in mixtures of DMSO/water. <br /><br />But lots of other good points are raised.Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-91526031864264492872024-01-17T06:37:38.979-08:002024-01-17T06:37:38.979-08:00One can have a different look also - how often agg...One can have a different look also - how often aggregates flat the apparent activity of a compound, limiting the free compound concentration? Could be a problem with fragments, whenever high concentration is needed - could be a problem with advanced leads, especially in cellular assays. Examine your concentration-response curves critically!Enzymologistnoreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-20151002928523484792024-01-09T06:04:57.203-08:002024-01-09T06:04:57.203-08:00Thanks Pete and happy New Year to you too. What wo...Thanks Pete and happy New Year to you too. What would the use of residuals look like for kinact/KI in this case?Dan Erlansonhttps://www.blogger.com/profile/07927082337051189270noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-61211826365375864722024-01-08T08:10:06.071-08:002024-01-08T08:10:06.071-08:00Hi Dan and happy New Year. It is also possible to ...Hi Dan and happy New Year. It is also possible to define ‘bang for buck’ (extent to which activity beats a trend) for irreversible inhibitors. The use of residuals to normalize of affinity with respect to molecular size that I suggested in <a href="https://doi.org/10.1186/s13321-019-0330-2" rel="nofollow">NoLE</a> can also be used for other measures of activity (e.g., k.inact/K.i and other risk factors (e.g., logP). Peter Kennyhttps://www.blogger.com/profile/12180360326821860667noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-35329803060246281382023-12-18T23:31:39.794-08:002023-12-18T23:31:39.794-08:00Of course it is one of the most highly anticipated...Of course it is one of the most highly anticipated year-end tradition! Thanks for this great post.Sarahhttps://www.blogger.com/profile/17085365364001204144noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-60863766137468483842023-12-03T13:14:19.770-08:002023-12-03T13:14:19.770-08:00Yes it was great to see validation of this PAINS c...Yes it was great to see validation of this PAINS chemotype. In a similar category to the pyrrole benzoic acids in some ways. The latter produce bioactive anionic polymers on standing and purified material loses all activity.Jonathanhttps://www.blogger.com/profile/05431411410781254400noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-76986218401973275542023-11-28T08:03:40.452-08:002023-11-28T08:03:40.452-08:00I’d actually be very wary of THQs fused with cyclo...I’d actually be very wary of THQs fused with cyclopentene (the presence in a molecular structure of a hydrogen that is simultaneously benzylic and allylic would ring alarm bells for me) even if I had been unaware of the instability that the authors have discovered and I don’t think that you’d lose exploitable chemical diversity by not screening this chemotype. What I was getting at in my initial comment is that the authors make statements about fused THQs and tricylic THQs (e.g., “Tricyclic tetrahydroquinolines (THQs) are a family of lesser studied pan-assay interference compounds”) when instability has only been shown to be an issue when the fusion of THQ is with cyclopentene. Nothing presented in this study would make me worry about a fused THQ that lacked the double bond in the ‘third’ ring. Peter Kennyhttps://www.blogger.com/profile/12180360326821860667noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-74167185686992973542023-11-28T03:56:48.890-08:002023-11-28T03:56:48.890-08:00Hi Pete,
The authors do mention that fused THQs wi...Hi Pete,<br />The authors do mention that fused THQs without the cyclopentene do not decompose, and even include this in the graphical abstract. Do you feel that fused THQs containing the isolated double bond are useful chemical starting points, and that by discouraging work on them valuable chemical diversity might be lost?Dan Erlansonhttps://www.blogger.com/profile/07927082337051189270noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-63180677608336672172023-11-27T10:45:12.617-08:002023-11-27T10:45:12.617-08:00Hi Dan, I’ll be brief since I’ve actually been wor...Hi Dan, I’ll be brief since I’ve actually been working on a post on this article over the last couple of days (hopefully be done later this week). The observed instability is certainly of interest and the information should be helpful for anybody considering the progression of compounds that incorporate this scaffold. The authors seem to be suggesting that the risk is associated with all fused THQs and I don’t think that their results support this view. Although chemical stability would (or at least should) certainly be a show stopper, I don’t think that the authors have convincingly demonstrated that compounds incorporating the cyclopentene-fused THQ scaffold exhibit pan-assay interference as a compound class (or even that they interfere with individual assays). The authors appear to be misrepresenting reference 2. Peter Kennyhttps://www.blogger.com/profile/12180360326821860667noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-71380236732279718532023-11-02T07:22:01.255-07:002023-11-02T07:22:01.255-07:00Further information about the 461 fluorine library...Further information about the 461 fluorine library is available through Key Organics (https://www.keyorganics.net/bionet-products/fragment-libraries/) as the BIONET Fluorine Fragment Library.Andrew Lowersonnoreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-26407292412988596942023-11-01T21:43:45.444-07:002023-11-01T21:43:45.444-07:00Hi Christophe,
That's a cool paper but it'...Hi Christophe,<br />That's a cool paper but it's a little different as the compounds discussed in the 2018 paper bind to SOS1 rather than RAS, though they do share structural similarities!Dan Erlansonhttps://www.blogger.com/profile/07927082337051189270noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-90697091147327213982023-10-30T20:01:49.589-07:002023-10-30T20:01:49.589-07:00Note that Steve Fesik published a follow up to his...Note that Steve Fesik published a follow up to his 2013 paper in 2018. See "Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling" in J Med Chem 61: 6002. Link: https://doi.org/10.1021/acs.jmedchem.8b00360<br />The best compound had an EC50 of 0.8 microM.Christophe L Verlindehttps://faculty.washington.edu/verlinde/noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-83443144182436251122023-10-29T11:18:15.309-07:002023-10-29T11:18:15.309-07:00Hi Pete,
Unfortunately the paper is behind a paywa...Hi Pete,<br />Unfortunately the paper is behind a paywall, but I'd be curious to get your thoughts on the Liability Predictor itself, which is not. You are correct that it won't pick out problems due to UV/vis absorption etc., but what I like is that in theory it shows which assays a given compound may show false-positive behavior. As you point out the training set may be too small, but it is odd that even compounds specifically described in the paper as being problematic seem to pass the online filter.Dan Erlansonhttps://www.blogger.com/profile/07927082337051189270noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-79027856257375543072023-10-25T12:59:48.595-07:002023-10-25T12:59:48.595-07:00Hi Dan, I can’t actually see the article and will ...Hi Dan, I can’t actually see the article and will make some general comments. The authors state in the abstract that they “… developed and validated quantitative structure–interference relationship (QSIR) models to predict these nuisance behaviors. The resulting models showed 58–78% external balanced accuracy for 256 external compounds per assay.” I take “quantitative” to imply that continuous data have been used to build regression models but “external balanced accuracy” suggests the models are actually categorical. I’m assuming that the four assays that they’ve run all measure nuisance behavior directly (PAINS filters are based on assumptions that frequent-hitter behavior in the assay panel is indicative of nuisance behavior) and these will not detect nuisance behaver resulting from UV/vis absorption, fluorescence, singlet oxygen reactivity/quenching or colloidal aggregation. Interference with read-out increases with concentration and here’s a relevant <a href="https://doi.org/10.1177/1087057106286653" rel="nofollow">article</a> from my former AZ colleagues that shows how interference can be assessed and in some cases corrected for.<br /><br />My view is that QSAR (or ML) models cannot make reliable predictions if they’ve not been trained with data for close structural analogs of the compounds for which predictions are being made and it may be that there’s nothing that is similar to toxoflavin in the data sets used to train the models. One simple way to address this issue is to present the user with the relevant data for the compounds from the training set which are considered to be the closest neighbours of the compound for which the prediction has been made (for some reason QSAR/ML modellers appear to consider this a terrible idea). Uneven coverage of chemical space by training and test sets is a real (although rarely acknowledged) problem in QSAR/ML modelling and my view, expressed in this 2009 <a href="https://doi.org/10.1016/j.bmcl.2008.12.003" rel="nofollow">article</a> is that some (most?) “global” models are actually ensembles of local models. Another consequence of uneven coverage of chemical space by training/test sets is that validation procedures can lead to optimistic assessments of model quality. <br />Peter Kennyhttps://www.blogger.com/profile/12180360326821860667noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-74493739724323436092023-10-22T21:37:04.225-07:002023-10-22T21:37:04.225-07:00Hi Pete,
The idea of a more flexible molecule havi...Hi Pete,<br />The idea of a more flexible molecule having lower molecular complexity than a rigid molecule is interesting, and further illustrates the complexity of trying to come up with a metric. Perhaps the problem is even more devilish than Justice Potter's famous quote about "knowing it when I see it."Dan Erlansonhttps://www.blogger.com/profile/07927082337051189270noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-39163570132450554082023-10-20T13:59:49.138-07:002023-10-20T13:59:49.138-07:00I certainly agree with your assessment of the Hann...I certainly agree with your assessment of the Hann model, Dan, and also that it would be useful to be able to quantify molecular complexity. To be useful in selection of compounds for screening I’d conjecture that a molecular complexity metric would need to ‘know’ something about interaction potential of heteroatoms (hydroxyl is arguably contributes more to complexity than ether oxygen because both HBD and HBA need to be accommodated by the binding site). The Hann view of complexity also has relevance beyond binding of ligands to targets (I invoked it in the aqueous solubility section of this <a href="https://doi.org/10.1021/acs.jmedchem.2c01147" rel="nofollow">article</a> in the context HBD-HBA imbalance). I’ve found it useful to control extent of substitution when selecting fragments for screening (here’s an ancient <a href="https://fbdd-lit.blogspot.com/2009/01/molecular-complexity.html" rel="nofollow">post</a>) although I don’t think that it would be possible to define a useful metric in these terms (nevertheless I’d be delighted to be proven wrong on this point).<br /><br />Having more than one significantly populated conformation would increase the probability of a good match with the binding site and, in the Hann model, this would be equivalent to being of lower complexity than an ‘equivalent’ ligand which only had a single significantly populated conformation. My view is that it would be difficult to account for conformational flexibility in a meaningful manner when attempting to quantify molecular complexity although, as said before, I’d be delighted to be proven wrong on this point.<br />Peter Kennyhttps://www.blogger.com/profile/12180360326821860667noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-58882863535793057922023-10-19T21:20:52.028-07:002023-10-19T21:20:52.028-07:00Hi Pete,
I mostly agree with you. I do like the id...Hi Pete,<br />I mostly agree with you. I do like the idea of having a quantitative measure of molecular complexity since the Hann model is more a qualitative thought experiment. But as you, "Wim," and I have noted, this seems difficult to do in a useful, non-arbitrary fashion.<br /><br />I do disagree with your example though. Consider 1-bromo-4-methylbenzene vs cis-1-bromo-4-methylcyclohexane. I would argue the second molecule is more "complex" than the former, if for no other reason than that it can assume more conformations. That said, I have no idea how "much" more complex it is.Dan Erlansonhttps://www.blogger.com/profile/07927082337051189270noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-87479399422914367902023-10-19T03:06:13.494-07:002023-10-19T03:06:13.494-07:00Hi Dan,
This way of looking at molecular complex...Hi Dan,<br /> <br />This way of looking at molecular complexity is very different to that of Mike Hann and colleagues and it’s not clear where (or even whether) it would fit usefully into drug discovery. The Hann model is framed in molecular recognition terms and the key point is that is that the likelihood of each pharmacophoric feature interacting optimally (dare I say efficiently?) with the target decreases with the number of pharmacophoric features in the molecular structure of the ligand. As with Ro5, the Hann model raises of awareness of factors that you need to consider when selecting compounds for screening.<br /><br />Although I see advantages from a molecular recognition perspective in having tetrahedral carbons in rings (especially when substituents adopt axial orientations naturally) I’ve always regarded the link between Fsp3 and molecular complexity as rather flimsy. For example, I wouldn’t regard a 1,4-disubstituted benzene ring as any less complex than the equivalent cis-1,4-disubstituted cyclohexane (although the latter will give you access to the region ‘above’ the ring plane). Neither SPS nor nSPS appears to be usefully predictive of biological activity (the trends were observed in structurally diverse data sets and binning of the data suggests that these trends are very weak) and this study wouldn’t persuade me to change the way that I do things. I would speculate that (as is the case for Fsp3) that SPS and nSPS values would tend to be higher for molecular structures with basic centers than those without. <br />Peter Kennyhttps://www.blogger.com/profile/12180360326821860667noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-90380890608066574192023-10-18T13:00:43.788-07:002023-10-18T13:00:43.788-07:00Because complexity is a very subjective thing, it ...Because complexity is a very subjective thing, it makes sense a lot of things about this specific score are quite ad hoc too. In a way, this score is like a weighted version of the Zagreb M1 topological index, which is simply the sum of each atom's (heavy atom) degree squared. In my opinion, the main strength of the result here is that "normalizing" (dividing the score by atom count) makes the score independent on the molecule size, though that is a kind of obvious consequence: nSPS is actually just the average of the atom per atom SPS.<br /><br />As the atom's SPS depends only on degree, hybridization, stereo-flag and non-aromatic ring-membership, this is really an atomic descriptor as it does not depend on the environment or on long range co-occurrences in the molecule at all. I quite strongly agree that the categories and their weighing are very ad hoc: is a quaternary sp3 carbon n_i2=16 times more complex than a methyl carbon? Perhaps, but perhaps it could be 5 times or 20 times. Is an sp-hybridized atom less complex than an sp2 atom? And doesn't the degree term already account for this? All of this seems to be based on vibes and having a simple formulation (which is not a criticism!).<br /><br />To give an example where nSPS clearly fails the intuitive test, try this: nSPS of Dynemicin A, an enediyne natural product, a structure which has haunted total synthesis aficionados for years, with decalin, a commodity chemical. Dynemicin A has nSPS=30.5 and decalin=40.8. Why? Well, decalin is a fully sp3 framework, where every atom is in a ring, and where 20% of the atoms are stereogenic.<br /><br />Finally, one question remains to be answered: though the fundamental interest of molecular complexity is enough to justify this work and related work, what can medicinal chemists use a complexity score for? The authors show the correlation of nSPS with synthesizability is weak, so it's not that. They show nSPS for marketed drugs does not increase over time, so it's also not that. So then what is it? <br /><br />All this said, I was pleasantly surprised to see this get so much resonance and I am always happy to see cheminformatics, chemical graph theory and similarly fundamental approaches have their moment in the spotlight in the medicinal chemistry literature, so cheers to the authors and the editors!Wimhttps://www.blogger.com/profile/09810068574669196899noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-2641368429300524732023-10-02T08:20:05.664-07:002023-10-02T08:20:05.664-07:00Thank you Dan for elegantly summarizing a few diff...Thank you Dan for elegantly summarizing a few different talks but leaving the reader wanting for more. Yes we now need to wear sneakers at the conference to manage all the running around between session rooms. But the on-demand viewing of most talks is a true technology boon. My head is spinning with ideas for the DDC 2024 in San Diego. See you there!Tanuja Koppalhttps://www.blogger.com/profile/12904064776487028652noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-88249673806265646002023-09-11T20:31:47.152-07:002023-09-11T20:31:47.152-07:00Hi Pete,
I agree this could be characterized as sc...Hi Pete,<br />I agree this could be characterized as scaffold-hopping or fragment replacement but the authors themselves referred to it as fragment-linking, and they did computationally rebuild the linker.<br /><br />I also agree that the hydroxyl on L4 is problematic; your suggestion or a methoxy would have been better choices.<br /><br />Unfortunately the carboxylic acid seems to be important as methyl esters were less active in vitro and still not effective against the parasite. That said, P218 also has a carboxylic acid so it is a bit surprising that compound 8 is so much worse.Dan Erlansonhttps://www.blogger.com/profile/07927082337051189270noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-26908557915077776122023-09-11T12:43:06.823-07:002023-09-11T12:43:06.823-07:00Hi Dan, I see this study more as an exercise in sc...Hi Dan, I see this study more as an exercise in scaffold-hopping than fragment-linking given that P218 is a known high potency compound. If it were my project, I’d want to know how important, the carboxylic acid is for activity since it’s a substructural feature that can make it difficult for compounds to be orally absorbed and to get into cells. My view is that some (probably a lot) of the loss of potency going from P218 to L4 is due to a likely change in ionization state and I’d argue that 2,4-diamino-5-methoxypyrimidine (pKa: 7.2 at 20°C | JOC 1969 34 821–836 https://doi.org/10.1021/jo01256a011) is a more appropriate potency reference than L4 (likely to be neutral under physiological conditions). I don’t have access to the article so it is just possible that the authors discussed some of these points.Peter Kennyhttps://www.blogger.com/profile/12180360326821860667noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-46799050403704161152023-09-11T12:38:00.378-07:002023-09-11T12:38:00.378-07:00This comment has been removed by the author.Peter Kennyhttps://www.blogger.com/profile/12180360326821860667noreply@blogger.comtag:blogger.com,1999:blog-1136153439451224584.post-32834514895565306372023-08-22T10:48:42.252-07:002023-08-22T10:48:42.252-07:00As a former NMR spectroscopist, I like this easy l...As a former NMR spectroscopist, I like this easy ligand-observed R2KD method for Kd values of 10-1000 µM. I wonder if this an alternative or will replace the NMR titration. I am sure R2KD will become widely adopted and have great applications in drug development. Anonymousnoreply@blogger.com