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ean fsp 3 values dropped from 0 34 to 0 31 between 2000 and 2006 or so coinciding with the increasing popularity of metal mediated cross coupling reactions during that period since then fsp 3 has risen to 0 40 in 2024 which could be due to the focus on escaping flatland as well as the increasing availability of saturated building blocks and new synthetic methodologies consistent with the original publication the average fsp 3 increases as molecules progress through development from 0 34 overall to 0 36 for those that go into rat pharmacokinetic studies and to 0 38 for preclinical candidates close to the 0 39 found for drugs approved since 2009 according to the study last year a key correlation proposed in the original flatland publication was that solubility increased with fsp 3 and this was observed again here of 435 280 compounds having fsp 3 between 0 00 0 70 with measured solubility data 55 of those with more aromatic character had low solubility while only 15 of those with fsp 3 0 65 were poorly soluble the correlations held for solubility at neutral ph as well as at ph 2 molecules with lower fsp 3 also tended to have more aromatic rings and this has previously been shown to lower solubility in contrast to solubility lipophilicity logd did not correlate with fsp 3 among 503 780 compounds apparent permeability showed a complex and noisy correlation for 16 570 compounds leading the researchers to conclude that fsp 3 is not a good parameter to optimize p app inhibition of three cytochrome p450 enzymes cyp 3a4 2c8 and 2c9 was examined for 51 760 compounds weak trends were observed for the latter two with highly aromatic compounds being more likely to inhibit the enzymes but no trend was seen for cyp 3a4 inhibition of human ether a go go related gene herg is a major red flag for compound progression and here there was a correlation with higher fsp 3 compounds showing lower inhibition this trend held for both aminergic and nonaminergic molecules though as with solubility these trends could be driven by aromatic ring count which has independently been correlated to herg inhibition since the 2009 flatland publication many solvents have been spilled to replace phenyl rings with more shapely non aromatic moieties the researchers looked at matched molecular pairs for internal compounds to see what effects these changes had on solubility simply saturating a phenyl to a cyclohexyl ring tended to decrease solubility while the best solubility improvements resulted from cyclopropyl or isopropyl substitutions but these swaps did little for shapeliness of the eight substitutions for which sufficient data existed cyclopropyl and isoprproyl had the lowest increase of average fsp 3 as the researchers note using fsp 3 without consideration of other properties is not a good strategy to optimize solubility overall this study suggests that leaving the comforts of flatland may be worthwhile molecules with higher fsp 3 values are sometimes more challenging to synthesize but this itself can lead to new intellectual property space it s worth emphasizing that the correlations between fsp 3 and solubility cyp inhibition and herg inhibition are limited in the end the researchers recommend considering fsp 3 in combination with other factors in medicinal chemistry optimization as its standalone effect on specific properties is modest just as general risk factors won t predict whether any given person will contract a disease metrics won t predict whether any given molecule will succeed or fail as a drug posted by dan erlanson at 6 31 am 2 comments labels 3d aromatic computational library design metrics saturation 27 july 2026 ligand affinities for isolated proteins vs in cells and cell lysates earlier this year we highlighted a study that compared the affinities of kinase inhibitors for isolated proteins vs those same proteins in cells and found differences sometimes dramatic a new open access paper in j am chem soc by blake peterson and colleagues at ohio state university addresses the same question and explores insights from cell lysates as well to measure affinity in cells the earlier paper used nanobret which relies on a fusion protein consisting of the kinase and a luminescent protein it is possible that this artificial protein may behave differently from the native protein so the peterson group developed the fluorescent probe cellular binding assay fpcba this technique makes use of a fluorophore conjugated to a ligand for the protein of interest the protein of interest is overexpressed the binding of fluorescent probe causes cells to become fluorescent and the level of fluorescence can be quantified using flow cytometry adding a non fluorescent ligand displaces the fluorescent probe which is rapidly effluxed and the loss of fluorescence can be used to calculate the affinity of the ligand for the sake of brevity i m skipping lots of important details such as detailed characterization of efflux and use of a second fluorescent protein to correlate expression of the target but these are described extensively in the paper the researchers focus on a fluorescent probe based on dasatinib an approved drug that binds to dozens of kinases the researchers compared the affinity of dasatinib and imatinib another approved drug to the kinase abl1 using both fpcba and nanobret the results were reassuringly similar though dasatinib bound 3 or 4 fold more tightly in the pbcba assay than the nanobret assay while imatinib bound up to 2 fold less tightly which might be due to changes in the regulatory mechanism of the abl1 fusion protein required for nanobret whole cell assays tend to be lower throughput so cell lysates are often used instead for kinases a common assay makes use of kinobeads native kinases are captured from cell lysates on beads and quantified using mass spectrometry an inhibitor blocks binding of the kinase to the bead and this reduction in binding can be used to calculate the affinity the researchers measured the affinity of dasatinib and imatinib against a score of kinases using both fpcba and kinobeads of 21 kinases 14 showed similar affinities within four fold for dasatinib by both fpcba and kinobeads six of the remaining seven showed up to 13 fold tighter binding in fpcba than kinobeads which the researchers attribute to the kinases being in a more active state in cells than in lysates a similar phenomenon has been seen for the helicase wrn in contrast the kinase src showed 11 fold weaker activity in cells than lysates which the researchers attribute to autoinhibitory regulation the situation becomes even more discordant when comparing affinities in cells to the affinities of isolated recombinant kinase domains using the kinomescan assay since a picture is worth several hundred words the length of this blog post i ve graphed the results while possible to see a correlation it is also possible to see dragons in the shapes of clouds the affinity of dasatinib was generally higher often by more than 10 fold in the kinomescan than the fpcba assay which is not surprising given the lack of atp in the biochemical assay but there were exceptions most notably epha4 which binds slightly more tightly to dasatinib in cells than in the kinomescan assay interestingly the affinity in the cell lysate assay was lower the researchers suggest that in cells the kinase is in a more active form than it is in lysates perhaps due to membrane localization in the end this paper is another useful reminder that assays with isolated proteins do not necessarily translate to cells and of course activity in cells does not necessarily translate to activity in vivo understanding why is part of what makes drug discovery both frustrating and exciting posted by dan erlanson at 5 46 am no comments labels kinase selectivity 20 july 2026 differential scanning fluorimetry dsf for covalent ligands differential scanning fluorimetry dsf also known as a thermal shift assay is one of the most common techniques for fragment screening according to the most recent methods poll on practical fragments this popularity is in part due to the simplicity of the assay just mix your protein with a dye such as sypro orange which binds to the hydrophobic core of unfolded proteins heat the solution in a pcr thermocycler and measure the change in fluorescence ligands that bind specifically to proteins often stabilize them increasing the melting temperature as we noted in 2017 some companies even use dsf to assess the ligandability of new targets most of the focus on dsf has involved non covalent ligands but the approach also works for covalent ligands according to a new open access paper in the british journal of pharmacology by nir london and colleagues at the weizmann institute of science the researchers acknowledge that they are not the first to explore dsf on covalent ligands last year we discussed a screen of 47 covalent fragments against 47 kinases and just last month we highlighted a dsf screen that identified an unexpectedly covalent fragment hit the new paper starts by performing dsf on five drug targets btk the g12c mutant of kras sars cov 2 mpro pin1 and keap1 each with well characterized covalent ligands for example ibrutinib acalabrutinib and evobrutinib for btk sotorasib and adagrasib for kras g12c etc for four of the proteins they also tested non covalent or covalent reversible ligands almost all of the ligands increased thermal stability of the bound protein and covalent ligands tended to have a greater effect in addition to testing specific ligands the researchers also performed dsf experiments on the five proteins with three reactive non specific covalent ligands iodoacetamide ethyl 2 bromomethyl acrylate and a chloroacetamide called ra13 intact protein mass spectrometry confirmed that these molecules gave essentially complete modification of the five proteins in some cases at multiple sites in contrast to the specific ligands the reactive alkylators tended either to have marginal effects on the melting temperatures of the proteins or to actually destabilize the proteins sometimes dramatically that said there were cases of stabilization the researchers suggest that reactive non specific irreversible binders may act as destabilizers since they form an irreversible covalent bond regardless of molecular recognition which may result in deformation of the protein if the rest of the binder cannot be accommodated near the modified amino acid to assess how well dsf works for covalent fragments more generally the researchers acquired 2612 acrylamides from enamine and screened them each at 8 µm in pools of 5 against keap1 for 24 hours at 4 ºc mass spectrometry showed that just over 100 gave at least 50 modification which a back of the envelope calculation suggests a covalent efficiency roughly 1 m 1 s 1 next 84 compounds with differing degrees of modification were tested by dsf and in contrast to the kinase paper we discussed last year there was a correlation between extent of modification and either stabilization or destabilization of the protein but consistent with the specific ligands discussed above the more reactive fragments as assessed by glutathione reactivity were the only ones that caused destabilization the authors conclude by proposing dsf as a fast and complementary follow up approach for electrophilic fragment screening to prioritize productive and selective covalent binders over promiscuous reactive fragments this seems reasonable what do you think posted by dan erlanson at 5 55 am no comments labels biophysics covalent dsf fragment finding irreversible thermal denaturation thermal shift 13 july 2026 fluorine nmr meets make on demand libraries last month practical fragments wrote about make on demand libraries such as those offered by enamine we ve also written about fluorine detected nmr screening of fragments which is both rapid and particularly sensitive for low affinity binders a new paper in chemmedchem by patrick penner anna vulpetti and colleagues at novartis combines these two concepts the researchers had previously built a library of 5472 fluorinated fragments these were compared with the 77 billion molecules then in enamine real space which are based on a smaller set of building blocks that can be combined using validated chemistries more than a third of the novartis library members could be found in real space and nearly 80 had close analogs supporting the notion that one could do rapid follow up studies of fragment hits without requiring resource intensive in house chemistry to test whether this would work in practice the researchers turned to embryonic ectoderm development protein eed an oncology target that novartis has been pursuing for some time here s a 2017 post an undisclosed number of known fragment ligands were screened against enamine real space using three computational methods a search of the 180 000 enamine building blocks themselves spacemacs to find close analogs and fastrocs to find more distant analogs of 150 compounds ordered across the three categories 125 arrived 66 building blocks 30 close analogs and 29 distant analogs all of these were first tested by spr and nine mostly close analogs showed at least double digit micromolar binding to assess whether 19 f nmr could identify weaker binders the remaining 116 compounds were screened in mixtures of nine each this led to 43 additional hits of which several were characterized in more detail by competing them in a dose response format against a reporter molecule to calculate dissociation constants one of these came in at sub micromolar affinity though it was a close analog of a known binder the others were high micromolar two of the more novel and less potent molecules were used as starting points to select new molecules from enamine real space and 74 of the 81 selected were delivered and tested by spr or dsf two of these were more potent than the starting molecules one of them by more than an order of magnitude in the end although the results are modest the paper provides a detailed framework for applying fluorine nmr to make on demand libraries and with only four authors it seems to be a low effort approach although this work was done at novartis it should be suitable for smaller companies or academic labs that have access to an nmr posted by dan erlanson at 4 33 am no comments labels 19f fluorine fragment finding library design nmr 06 july 2026 fragment events in 2026 and 2027 we re half way through 2026 but there are still some good events ahead and 2027 is already starting to take shape september 14 16 fragments x rsc bmcs tenth fragment based drug discovery meeting will be held in the original cambridge uk you can read my impressions of the 2024 meeting the 2013 meeting and the 2009 meeting september 28 to october 1 chi s twenty fourth annual discovery on target will be held as always in brilliant boston as the name implies this event is more target focused than chemistry focused but there a...