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the main protease 3cl pro or mpro of sars cov 2 was the first target pursued in the fight against covid 19 a crystallographic fragment screen was conducted just weeks into the pandemic yielding dozens of hits some of these such as compound 1 formed covalent bonds to the active site cysteine compound 2 bound noncovalently nearby in the new paper the researchers used the program delinker a graph based deep generative method to try to link them just three linked molecules were made and tested each with a different amide connectivity while two were quite weak compound 5 showed low micromolar activity this is especially impressive given that both compounds 1 and 2 themselves were inactive sar studies revealed that the nitrile warhead is essential for activity and a crystal structure of compound 5 bound to 3cl pro confirmed covalent binding surprisingly though the structure showed that the moiety derived from compound 2 binds in a flipped position relative to the non covalent complex further fragment growing led to compound 28 the most potent compound described in the paper the researchers also tried warhead swapping replacing the reversible nitrile warhead with a chloride for irreversible aromatic nucleophilic substitution although some of these molecules showed activity the best was about 30 fold less potent this observation makes sense as the cysteine sulfur atom must take different trajectories to react with the different warheads as the researchers point out more potent inhibitors of 3cl pro have been reported the approved drug nirmatrelvir targets this enzyme however the paper is still a rare example of fragment linking starting from a covalent fragment see here for fragment merging on a different target personally what i find most interesting is the fact that it took just three molecules to go from inactive fragments to a low micromolar inhibitor but given that this molecule binds in a somewhat different manner than predicted perhaps a high throughput approach such as direct to biology would generate even more potent molecules posted by dan erlanson at 6 43 am no comments labels covalent crystallography fragment linking modeling 14 june 2026 vast fields of biologically active chemical space exactly 17 years ago i highlighted a paper from brian shoichet s lab in which he hypothesized that only tiny regions of chemical space are biologically relevant if so practical fragments quoted a major reason why the screening of synthetic compounds ever finds notable hits is that our libraries are biased toward the sort of molecules that proteins have evolved to recognize the best scientists continually question their assumptions and this is exactly what brian bryan roth and collaborators at university of california san francisco and university of north carolina at chapel hill have done in a new open access j med chem paper the idea that molecules more closely resembling metabolites and natural products would be more likely to be biologically active is reasonable given the promiscuity of many naturally occurring molecules as the researchers point out dopamine signals through 5 receptors while serotonin binds to 14 nature is the ultimate recycler constantly reusing chemical motifs but since 2009 there has been a massive growth of make on demand libraries and these have increasingly diverged from known molecules brian has been among the most prolific explorers of this new chemical space and as he noted in his keynote at ddc 2026 these gargantuan libraries are yielding more hits against more targets are these hits more selective in other words are molecules that are less bio like likely to bind to fewer targets this is the question the new paper addresses focusing on the 5 ht 2a serotonin receptor 5 ht 2a r the target for a variety of drugs including psychedelics the researchers have extensively studied this gpcr we wrote about a successful computational screen here in the new paper the researchers compared hits from a previous make on demand mod library screen of 1 6 billion molecules with a new screen of 3 5 million in stock molecules as predicted the in stock compounds were much more bio like than the mod compounds as assessed by several metrics tanimoto similarity avalon fingerprints and rdk7 fingerprints for the cheminformatics aficionados among you both libraries were computationally screened using dock3 8 against 5 ht 2a r of the top scoring hits 85 molecules from the in stock library and 384 molecules from the mod library were tested in a radio ligand displacement assay hit rates were nearly identical at around 24 each functional assays revealed the hits to be active with some acting as agonists while others were antagonists when tested against related gpcrs specifically 5 ht 2b r and 5 ht 2c r the in stock molecules were more promiscuous than the mod molecules but when tested against a panel of 318 gpcrs there were no differences the in stock molecules bound on average 1 7 of the receptors while the mod molecules bound on average 2 1 the similar promiscuity persisted even when focusing on the 55 aminergic gpcrs 5 ht 2a r is an aminergic gpcr in fact the most promiscuous compound of all came from the mod set and is distinctly not bio like of course this is just one study but i suspect it will generalize in 2009 i questioned whether biologically relevant chemical space is really so sparse as i wrote then consider a vast field of some crop that can only be harvested by night there are lights scattered haphazardly throughout the field one might expect that the crops immediately under the lamp posts would be harvested more intensively than crops in darker parts of the field even if other areas are equally productive in this scenario the lamp posts reveal natural products and similar molecules but much or even most of unlit chemical space may also be biologically active it just hasn t been sampled yet there is grandeur in this view of chemical space which is supported by the new paper imagine yourself in the midst of the field on a moonless night turn on your headlamp and step forward in any direction drug leads glimmer as far as your light can reach posted by dan erlanson at 9 44 am no comments labels chemical space computational computational screening fbld fragment libraries gpcr library design virtual screening zinc 08 june 2026 an unexpected lysine reactive covalent fragment against a pleckstrin homology domain last week we highlighted a study in which an attempt to optimize a covalent fragment led to a non covalent fragment that bound in a different location a new open access paper in j med chem by david spring marko hyvönen and colleagues at university of cambridge is almost the inverse a surprisingly covalent binder from a conventional fragment screen the researchers were interested in pleckstrin homology ph domains the 250 or so ph domains in humans bind to the intracellular side of the plasma membrane by interacting with phosphoinositides such as pip3 blocking membrane recruitment could be useful for multiple diseases but the highly charged nature of the interaction the p3 in pip3 means three phosphate groups makes drugging ph domains difficult a perfect challenge for fragments the study focuses on the ph domain from bruton s tyrosine kinase btk an important oncology and immunology target with several approved drugs all of which bind to btk s kinase domain its ph domain was screened against 720 fragments using differential scanning fluorimetry dsf seven fragments stabilized the melting temperature by a whopping 5 degrees c or more crystallography was successful for compound 1 which surprisingly revealed that the ketone reacts with the terminal amine of lysine 12 which normally makes electrostatic interactions with two phosphates in phosphoinositides the crystal structure showed unoccupied space nearby subsequent fragment growing and optimization led to compound 24 with low micromolar affinity as assessed by dsf the researchers obtained some two dozen crystal structures which they were able to correlate with structure activity relationships sar all of the molecules formed the imine with k12 reducing the ketone to an alcohol abolished stabilization in dsf intact protein mass spectrometry was used for assessing sar and confirming that the covalent bond formation is reversible adding two fragments with different affinities led to the same distribution of products regardless of the order of addition of the fragments not surprisingly the reaction was faster at higher ph but nearly complete covalent modification still took place within an hour at ph 7 4 even at high compound to protein ratios the molecules largely gave single protein modification and two separate computational studies of the pk a values of the 15 lysine residues in the btk ph domain revealed that k12 is an outlier with a calculated pk a of 7 1 or 8 8 compared to an average of 10 5 or 10 8 for the others this means that k12 is largely unprotonated at physiological ph increasing its reactivity a similar analysis of four related ph domains suggested that the equivalent lysine residues also have anomalously low pk a values the fact that k12 is conserved across related ph domains does raise the question as to whether selectivity will be possible with this type of ligand also no in vitro adme properties are provided so it is not clear whether this warhead is advanceable i wish the researchers had explored other heterocycle alternatives to the furan moiety to assess the tunability of the reactivity perhaps those will come later overall though this paper is a nice case study where following up on unexpected observations identified a new approach for covalently targeting lysine residues as isaac asimov famously said the most exciting phrase to hear in science is not eureka but that s funny posted by dan erlanson at 6 21 am no comments labels covalent crystallography fragment finding fragment growing 01 june 2026 from covalent to noncovalent 14 3 3 modulator unintentionally the seven members of the 14 3 3 family act as hub proteins that bind to other proteins bringing them together or affecting their subcellular localization some of the client proteins such as estrogen receptor alpha er α are associated with diseases such as cancer and stabilizing the interaction with 14 3 3 could thus be useful therapeutically the idea is that a small molecular glue could bind at the interface between 14 3 3 and a client protein enhancing the interaction we ve written here here and here about successful examples both covalent and noncovalent an open access paper in acs med chem lett earlier this year by richard doveston and colleagues at university of leiscester starts with a similar strategy but ends up somewhere else entirely the researchers had previously found that wr 1065 the active metabolite of the approved drug amifostine can covalently bind to c38 of 14 3 3σ this is the same cysteine residue that had been targeted by michelle arkin and coworkers in 2019 using tethering disulfide bond formation between wr 1065 and 14 3 3σ enhances the affinity of er α for 14 3 3σ by a modest 2 8 fold in the new paper the doveston group made a small set of analogs in which the thiol was replaced by other warheads compound 7 containing an acrylamide improved the affinity of er α for 14 3 3σ by nearly two orders of magnitude from 206 to 2 8 nm but surprisingly mass spectrometry revealed no covalent modification indeed compound 7 was also active at low micromolar concentrations against the c38a mutant form of 14 3 3σ while wr 1065 was inactive an examination of the structure activity relationships sar revealed that the acrylamide was essential reducing the double bond abolished activity while replacing the amide nitrogen with an oxygen made it significantly less active removing the primary amine or replacing it with a hydroxyl or carboxylic acid was also not tolerated if compound 7 does not bind covalently to c38 how does it work surprisingly the molecule does not even bind at the interface between 14 3 3σ and er α indeed it shows additivity with a well characterized molecular glue fusicoccin a known to bind at the interface where exactly compound 7 does bind is uncertain a series of biophysical experiments suggests that it may stabilize the dimeric form of 14 3 3σ though the mechanism remains to be determined this paper is a useful reminder that as the authors conclude even rational design approaches can lead to unexpected outcomes sometimes a warhead does not behave as one posted by dan erlanson at 6 22 am no comments labels covalent molecular glue ppi stabilization 25 may 2026 fragments in the clinic vvd 214 just over two years ago we highlighted a new clinical candidate targeting wrn a covalent inhibitor then called vvd 133214 an open access paper published near the end of last year in j med chem from shota kikuchi david weinstein and colleagues at vividion describes in detail the optimization of the covalent fragment hit to the clinical compound shota presented some of this work at the 2024 ddc meeting this paper is also an interesting contrast to non covalent fragment finding approaches against this target we wrote about earlier this month the 2024 post described the chemoproteomic screening that identified compound 1a which covalently binds to c727 in wrn an early observation was that some molecules were cooperative with atp while others were competitive given the high concentration of atp in cells the researchers prioritized the former category which led to compound 1f note that while i m showing only the k inact k i values the researchers used biochemical and cell based assays to drive sar the vinyl sulfone warhead is unusual amongst covalent clinical compounds so the researchers sought to characterize it the rate of reaction with glutathione for compound 1f is comparable to the approved drug osimertinib reactive though acceptable to try to lower the reactivity and also prevent isomerization of the double bond the researchers introduced a methyl group compound 2a not only showed increased stability but also improved activity against wrn and sub micromolar activity in a cell based assay a crystal structure of a later molecule revealed interactions with a hydrophobic patch on the protein explaining the improvement in potency importantly the other enantiomer was much less potent other rings were tried unsuccessfully to replace the pyrimidine and the phenyl moieties however changing the cyclopentyl ring to a tert butyl moiety compound 5d further improved the potency to the point where the compound could be tested in vivo where it proved to be active in a mouse xenograft study mass spectrometry experiments revealed prolonged occupancy of c727 out to 24 hours after compound dosing even though the compound itself had been cleared consistent with a long half life of the wrn protein the researchers note that high target engagement te at 24 hours was predictive of tumor growth inhibition whi...