Protein–protein interactions
11 articles
A small-molecule BCL9/β-catenin blocker is tested in glioblastoma cells
- Because BCL9, a β-catenin coactivator, had lacked small-molecule inhibitors, its therapeutic value in glioblastoma had not been tested pharmacologically.
- The new inhibitor ZD37-28R was predicted by docking to bind β-catenin, and it disrupted the BCL9/β-catenin interaction in vitro.
- It suppressed β-catenin-driven transcription and reduced proliferation and migration of U87-MG and U251 glioblastoma cells.
Wnt/β-catenin has been a graveyard for small molecules, and a BCL9-selective PPI blocker is a more tractable angle than hitting β-catenin broadly. The open questions are the usual PPI ones: direct biophysical evidence of binding rather than docking, selectivity against other β-catenin partners, and brain exposure for a glioma indication. Treat this as target validation work, not a lead yet.
Dialing hERG out of a DCN1–UBE2M inhibitor without losing potency
- The earlier tool compound NAcM-OPT blocked the DCN1–UBE2M interaction, was orally available and slowed xenograft growth, but carried significant hERG affinity that stalled development.
- The authors systematically modified the scaffold to cut hERG binding while keeping DCN1 engagement.
- Lead compound 110 matched the parent in biochemical and cellular potency, with better physicochemical properties and improved selectivity against hERG.
This is the unglamorous but necessary second act: a validated PPI chemotype that was dead on cardiac safety, rescued by SAR alone. The takeaway for anyone with a basic, lipophilic PPI binder is that hERG can often be engineered out without giving up the pharmacophore, so check your own series before abandoning it.
mRNA-display macrocycle IMP2660 gives the first effector-free RAB27A structure
- mRNA display against the RAB27A effector-binding interface produced macrocyclic peptide hits, which were optimized into IMP2660.
- IMP2660 binds RAB27A tightly and disrupts RAB27A–effector interactions.
- Its co-crystal structure with active-state RAB27A, solved without any effector, maps the effector-binding surface for structure-guided design.
The crystallography chaperone angle is the underrated payoff: wild-type RAB27A only crystallized with its effector, so a clean macrocycle-bound structure unlocks soak-in and fragment work. Whether IMP2660 itself is more than a tool is another matter, since permeability for a nonapeptide-sized macrocycle against an intracellular GTPase is the obvious hurdle.
A potent macrocyclic peptide binder enables effector-free crystallization of the GTPase RAB27A ↗
HTS framework finds small molecules that block tau binding to the LRP1 receptor
- The team built a quantitative assay set around purified LRP1 ligand-binding domain 4, using fluorescence polarization, split luciferase and TR-FRET.
- Tau, RAP and a peptide ligand competed for overlapping binding sites with nanomolar-range affinities across formats.
- A screen on this platform identified small-molecule inhibitors of the interaction, a starting point against tau uptake and spread.
Protein–protein interactions with a receptor ectodomain are tough targets, so three orthogonal assays is the right way to weed out artifacts. I'd treat the hits cautiously until they show activity in cellular tau-uptake assays and clear LRP1's many other ligands, such as ApoE and RAP, without broad liabilities.
High-Throughput Screening Identifies Small-Molecule Inhibitors of the Tau-LRP1 Interaction ↗
mRNA-display macrocycles reveal CHD4 as an interaction hub in the NuRD complex
- mRNA display against CHD4's SANT-SLIDE domain yielded small macrocyclic peptides that block its interaction with GATAD2A, a core step in building the NuRD complex.
- The screen pointed to a second binding site on CHD4; CDK2AP1 was confirmed to bind there, and the CHD4–GATAD2A–CDK2AP1 ternary complex structure was determined.
- Disrupting NuRD induces fetal hemoglobin, a validated therapeutic strategy for sickle cell disease and other β-hemoglobinopathies.
One selection campaign delivering both hits and biology is a nice outcome. Macrocycles sitting on a protein–protein interface are rarely drug-like as they stand, so my question is whether the ternary structure lets us shrink them toward something cell-permeable; the second site on CHD4 gives another handle for that. I'd also want to see selectivity against related remodelers.
Scope library: a chemical space between fragments and full molecules for tractable hits
- Scope defines a chemical space between fragments and elaborated low-molecular-weight library compounds, emphasizing compound quality, ligand efficiency and selected property ranges to keep hits tractable for medicinal chemistry.
- Scope ring systems (ring-X-ring) organize the space and guide intentional functionalization toward low- to mid-micromolar potency; a roughly 10k-compound set suits medium-throughput SPR, native MS, DSF and biochemical screens.
- Case studies on trypanosomal CLK1, a 14-3-3/ERα molecular glue project and SARS-CoV-2 Mpro show comparable primary hit rates to diversity sets, with better ligand efficiency after counter-screening.
Honestly, the pitch I like here is hits you can actually start working on: a library sitting between fragments and full-size compounds, built around ligand efficiency, with ring-X-ring cores that tell you where to functionalize next. A 10k set fits SPR, native MS and DSF, so a smaller group can run it. The open question is whether primary hit rates on par with diversity sets, with better LE after counter-screening, hold up beyond three targets, and how much the scaffold constraint narrows novelty.
Imidazolium Amino Acids Proposed as Bioisosteres for Methylated Lysine and Arginine Residues
- Imidazolium amino acids are proposed as cationic bioisosteres mimicking the size and charge of trimethyllysine, dimethylarginine, and arginine side chains.
- Binding to methyl-lysine reader domains is evaluated to see how closely the surrogates reproduce native residue recognition and selectivity.
- Cell assays indicate the charged isosteres can still traverse membranes, and SAR trends tie ring substitution to the affinity-permeability tradeoff for reader ligands and CPPs.
A non-hydrolyzable Kme3/Rme2 mimic solves a genuine headache—native methylated peptides get erased by demethylases or clipped by proteases mid-assay, muddying SAR. If ring substitution tunes affinity without killing permeability, this is a genuine alternative scaffold for reader-domain PPI inhibitors and arginine-free CPPs, not just another quaternary-ammonium curiosity—worth testing against our own Kme3 reader panel.
Stress-Testing AI Co-Folding Screens: Lessons from a Keap1–Nrf2 Case Study
- Multi-stage virtual screening cascades that combine AI co-folding models with learned-affinity (ML) scoring are now standard practice in computational drug discovery.
- Each stage's output score is typically taken at face value and used to advance or discard candidates without independent validation of what it actually captures.
- This preprint systematically evaluates, stage by stage, whether cascade scores provide the information practitioners need to trust them, using the Keap1-Nrf2 protein-protein interaction as a case-study target.
- The authors characterize failure modes that arise at different stages of the cascade, offering a quality-control perspective on where and why these pipelines can mislead.
Every screening campaign now runs some flavor of co-fold-then-ML-score cascade, and honestly most of us take the ranked list at face value because checking each stage is a pain. That's the exact habit this preprint is poking at, using Keap1-Nrf2 — a notoriously flat, shallow PPI interface that's already brutal for docking and pharmacophore methods — as a stress test where scoring artifacts should show up fast. If the abstract's framing holds, the real message isn't "don't use these tools," it's "don't trust a single composite score without knowing what each stage is actually measuring" — pose confidence, affinity ranking, and physical plausibility are not the same thing, and conflating them is how false positives sneak to the top. Worth revisiting once the full methodology and failure-mode breakdown are out; details here are still thin.
New "Scope" Chemical Space Yields Ligand-Efficient Hits Across Three Targets
- "Scope" describes a mid-sized (10k-50k compound) chemical space positioned between minimal fragments and fully elaborated low-molecular-weight libraries, designed to maximize ligand efficiency and medicinal chemistry tractability.
- The authors introduce "Scope ring systems" (ring-X-ring) as a core organizing concept for building libraries and guiding functionalization toward sufficient potency.
- A 10k-compound Scope screening set — evaluated by SPR, native mass spectrometry, DSF, and biochemical assays — matches general diversity sets' primary hit rates even at higher screening concentrations, while showing superior ligand efficiency and higher hit rates after counter-screening.
- Case studies on trypanosomal CLK1 kinase, a 14-3-3/estrogen receptor-alpha molecular glue project, and SARS-CoV-2 main protease show the set yields diverse, tractable, ligand-efficient hits across varied binding sites.
The "sweet spot between fragments and full libraries" pitch isn't new — DEL, FBDD, and house libraries have all claimed it before. What's actually new in Scope is the ring-X-ring organizing logic: forcing vectors off two ring systems rather than one flat scaffold gives a built-in growth vector for SAR from hit one, the part fragment campaigns usually bolt on later. The number that matters to me isn't the hit rate, it's "higher hit rate after counter-screening" — that's fewer SPR artifacts and aggregators wasting my week. The real test is the 14-3-3/ERα glue case: PPI/glue targets chew up conventional libraries because there's no deep pocket to reward LE. If a rigid, moderately-sized scaffold set can seed a glue hit, that's the transferability claim worth watching, not the Mpro or CLK1 wins.
Benchmark Study Reveals Blind Spots in AI-Based Virtual Screening for Keap1-Nrf2
- A new benchmarking study examines a virtual-screening pipeline that chains structure-based co-folding models with learned-affinity scoring, an increasingly common setup for computational hit-finding.
- The cascade was applied to the Keap1-Nrf2 protein-protein interaction, a notoriously hard-to-drug target due to its flat, polar interface.
- Instead of trusting only the final ranked output, the authors assessed each stage separately against experimentally meaningful signal.
- They identify specific points where a stage's score diverges from that signal, a failure mode that can mislead downstream compound prioritization.
- The paper proposes per-stage control checks practitioners can run before relying on a cascade's final hit list, framing the work as a methodology and reliability study rather than a report of a new inhibitor.
Keap1-Nrf2 is exactly the flat, polar PPI where a co-folding model will happily spit out a confident-looking pose and the affinity scorer will rank it #1 for the wrong reasons — so a paper that pries the cascade apart stage-by-stage is more useful to me than another "we found a hit" claim. What I actually want out of this: a checklist to run on my own vendor or in-house pipeline before I let its top 20 dictate what goes on the synthesis queue. If the co-folding confidence and the affinity score are quietly diverging, that's exactly the failure mode that burns weeks on compounds that never had real signal behind them. No new chemical matter here, no binding mode to chase — just a reminder that for a target this treacherous, the ranked list is not the QC step. Filed under "read before ordering," not "read for the inhibitor."
The Hidden Loop Guiding Malaria Invasion
- This is a perspective/analysis article, not a new experimental study, focused on Plasmodium falciparum apical membrane antigen 1 (PfAMA1) as an anti-malarial drug target.
- PfAMA1 binds rhoptry neck protein 2 (PfRON2) to form the moving junction that enables the malaria parasite to invade red blood cells, making this protein-protein interaction a key therapeutic target.
- Most structure-based inhibitor design has targeted the hydrophobic trough, a well-defined groove on PfAMA1 that accommodates the PfRON2 peptide.
- The authors highlight a domain 2 (D2) loop near the trough that shows cryptic, conformation-dependent dynamics rather than a fixed structure.
- They argue this loop flexibility, previously overlooked, meaningfully shapes how PfAMA1 recognizes PfRON2.
- The perspective calls for future anti-malarial drug design to incorporate D2 loop dynamics alongside the trough itself, rather than treating the binding site as static.
If I'd been designing against the trough alone, I'd have built a static pharmacophore off one co-crystal pose and wondered why my analogs kept losing potency in ways the model couldn't explain — that's the D2 loop talking. A cryptic, conformation-dependent element next to your primary pocket means the 'druggable groove' you're staring at in PyMOL isn't the whole binding event; you need ensemble docking or short MD runs to even see the states worth targeting, not another round of rigid-receptor SBDD. This is the same lesson from Bcl-2/Mcl-1 and MDM2-p53 campaigns — flexible loops or helices near a defined hot spot often carry the selectivity, not the anchor pocket. No new chemical matter here, but it's a real prompt to revisit our PfAMA1 series with loop-aware ensembles before writing off SAR gaps as noise.