GPCRs
16 articles
Cofolding models can place the ligand right while getting the protein conformation wrong
- AlphaFold3, RoseTTAFold3, Boltz-2 and Chai-1 were benchmarked on kinases and Class A GPCRs, families whose pharmacology depends on defined conformational states.
- Only complexes released after all four models' training cutoffs were used, plus one earlier control structure, to give a prospective test.
- Correct ligand placement turned out to be systematically decoupled from accurate prediction of the surrounding protein conformation.
For anyone docking into cofolded poses, this is the warning label: a plausible ligand pose does not mean the DFG state or GPCR activation state is right. That matters most for type II kinase inhibitors and biased GPCR ligands, where the conformation is the whole point. I'd treat cofolded structures as hypotheses to validate against known conformational markers before using them for SAR design.
Incyte's oral MRGPRX2 antagonist INCB187175 emerges from scaffold hybridization
- MRGPRX2 drives IgE-independent mast cell activation and is linked to urticaria, atopic dermatitis and pseudoallergic reactions.
- Scaffold hybridization and SAR gave pyrazolopyrimidine antagonists active in both Gq/IP1 and β-arrestin assays.
- Fixing solubility and CYP inhibition liabilities led to INCB187175, orally exposed across species, which blocked degranulation in primary human mast cells and mast cell activation in vivo.
Scoring on both Gq and β-arrestin readouts is the right call for a receptor where bias could muddy the pharmacology. The solubility and CYP fixes read like a practical optimization story, not a lucky hit. The crowded MRGPRX2 field means the real differentiator will be human exposure and how well mouse-proxy assays translate for a human-restricted receptor.
Discovery of Pyrazolopyrimidines as Potent and Orally Bioavailable MRGPRX2 Antagonists ↗
Fully G protein-biased GPR183 agonist TUG-2604 reaches oxysterol-like efficacy
- SAR optimization of earlier virtual-screening hits, themselves derived from the antagonist NIBR189, gave full GPR183 agonists with complete G protein bias.
- The lead, TUG-2604, matches the endogenous oxysterol 7α,25-OHC in potency and efficacy without recruiting β-arrestin2.
- It failed to drive human dendritic cell migration on its own and blocked migration induced by the oxysterol.
Turning an antagonist-derived hit into a full agonist with complete G protein bias is not routine, and the migration data hint that β-arrestin signaling carries the chemotaxis. For anyone weighing GPR183 in inflammation, this is a clean tool to separate the two arms before committing to a direction.
Development of Potent G Protein Pathway-Biased GPR183 Agonists ↗
Dual MOR/D3R ligand with a lower D3R/MOR ratio shows reduced abuse-related signals in mice
- Dual ligands fuse the MOR partial agonist TRV734 with a D3R-antagonist trans-cyclopropylamine scaffold, aiming at safer opioid analgesics.
- (R)-LS02-14 and TRV734 gave robust antinociception but similar abuse-liability and respiratory-depression signals.
- (R)-LS01-64, with a much lower D3R/MOR ratio, gave modest analgesia but weaker reinforcing and conditioned-reward effects and minimal respiratory impact.
The data argue that the D3R/MOR balance, not mere D3R engagement, sets the behavioral profile, and the best safety came with less analgesia. That is the familiar trade-off, so the open question is whether a ratio exists that keeps efficacy while retaining the reward-dampening effect.
Viatris to buy Pacira for about $1.65B to add non-opioid pain franchise
- Viatris agreed to acquire Pacira BioSciences in an all-cash deal at $36.50 per share, a premium of roughly 45% to the last close.
- The prize is Pacira's non-opioid products EXPAREL for post-surgical pain and ZILRETTA for knee osteoarthritis pain, plus a knee OA gene therapy candidate.
- Closing is expected by the end of 2026, funded mainly from cash on hand.
This is Viatris buying a commercial pain franchise rather than science, which fits its pivot from generics toward branded cash flow. The pairing with its pending fast-acting meloxicam decision hints at a non-opioid pain sales force, though EXPAREL's generic-style competition is the long-term risk to watch.
Viatris to snap up Pacira's non-opioid pain pipeline for $1.65B ↗
Bispecific GTACs antagonize GPCRs by sending them to the lysosome
- GPCR–TfR1 targeting chimeras (GTACs) are bispecific antibodies that pair a receptor binder with a transferrin-receptor binder.
- They drive endocytosis and lysosomal degradation of the GPCR, rather than blocking the orthosteric site.
- Reported for BILF1, RXFP1 and CCR6, covering viral, cancer and immune targets that are hard to drug.
- Signalling, including constitutive activity, was fully shut down, with markedly greater potency than conventional antibody antagonists.
Degrading the receptor sidesteps the usual GPCR headache of finding a clean orthosteric or allosteric small molecule, and it kills constitutive signalling that inverse agonists only partly touch. The catch for my own work: it is an antibody format, so oral exposure and tissue reach are off the table, and TfR1 recruitment brings its own distribution and safety questions. Still, it hands us a genuine alternative mechanism for orphan-like GPCRs where chemistry has stalled.
GPCR antagonism via rewiring of receptor trafficking and degradation ↗
What first-generation oral GLP-1 drugs teach about designing the next ones
- Reviews nonpeptidic GLP-1 receptor agonists that reached the clinic, including danuglipron, lotiglipron, DA-302168S and orforglipron, as case studies of how each solved the oral-delivery problem.
- Notes the design challenges these first-generation molecules still leave open.
- Proposes next-generation approaches: peptidomimetic design, multi-target agonists, and exploiting orthosteric-allosteric cooperativity.
- Covers practical aspects such as screening cascades, preclinical species choice, formulation and early safety assessment, with relevance to other difficult GPCRs.
Four clinical chemotypes, four different answers to the same problem: a class B GPCR built to bind a large peptide. What I want from a review like this is the SAR logic behind each survivor. Orthosteric-allosteric cooperativity is the idea I'd chase, since it could loosen the potency-versus-permeability tradeoff. Whether it holds up depends on the screening cascade and species choice, which is where programs usually stumble.
DT-9081: Scaffold Hopping Delivers an Oral EP4 Antagonist That Has Cleared Phase I
- EP4 blockade is an immuno-oncology idea built on PGE2-driven immune suppression in tumors.
- Scaffold hopping gave a new chemical series with better activity and pharmacokinetics, and SAR work led to DT-9081.
- It combines potent antagonism, favorable ADME and a clean preclinical safety profile, and has completed a phase I monotherapy trial in solid cancers.
This paper is the full med-chem story behind a compound that already has human data, which is rarer and more useful than most 'discovery of' papers. EP4 is crowded, so the interesting part is how the new series differentiates on PK and safety against earlier antagonists. I'd read it for the scaffold-hop logic and watch whether phase I translates into combination activity with checkpoint blockade.
Structure-Guided RXFP4 Agonists Stay in the Gut and Ease Constipation in Mice
- Guided by the cryo-EM structure of RXFP4, the authors built a tetrahydroisoquinoline agonist series aimed at two hurdles: close homology to RXFP3 and the need for gut-restricted exposure.
- Lead compound 44 was a potent agonist with strong selectivity over RXFP3 and a pharmacokinetic profile heavily skewed toward ileum over plasma.
- Oral dosing was effective in a loperamide-induced constipation mouse model.
Getting a small molecule onto a peptide-GPCR whose paralog looks nearly identical is the hard part, and using the cryo-EM structure to buy RXFP3 selectivity is the right play. The gut-over-plasma skew is what I'd look at first, since a locally acting agonist sidesteps systemic liabilities. I'd still want permeability, efflux and metabolic stability data behind that ileum exposure.
Triazole-Stapled Peptides Merge Opioid and NPFF Signaling for Long-Lasting Peripheral Pain Relief
- Two-step triazole stapling built a peptide from DN-9's opioid segment, then added an NPFF pharmacophore via chimeric conjugation to form a multitarget agonist.
- The opioid-only stapled peptide acts as a μ-opioid agonist with partial δ-opioid activity; the conjugate targets μ-, κ-opioid and NPFF receptors with G-protein-biased μ signaling.
- Subcutaneous dosing of both compounds produced sustained, dose-dependent analgesia in acute and visceral pain models.
Stapling DN-9's opioid core with triazoles to lock the bioactive turn, then bolting on an NPFF pharmacophore via chimeric conjugation, gets you μ/κ/NPFF polypharmacology without a small-molecule fragment-merging slog — clever scaffold logic. Layering G-protein-biased μ signaling on top of peripheral restriction stacks two independent side-effect levers in one peptide, though I'd want to see the stapling's SAR tolerance before calling it tractable.
Alkermes' Sleep-Drug Class Shows Early Promise Against ADHD
- Alkermes reported positive Phase 1b data for ALKS 7290, an orexin 2 receptor agonist, showing a substantial reduction in ADHD symptom scores after two weeks at the high dose, with the drug generally well tolerated.
- Cognitive and EEG-based biomarker tests also showed improvements in processing speed, working memory, and sustained attention.
- A Phase 2 study is now enrolling, with data expected in 2027.
Orexin agonists have mostly been a narcolepsy story (Takeda, Axsome); Alkermes just repositioned the same mechanism as a wakefulness/cognition play for ADHD, a market still dominated by stimulants and Qelbree-style non-stimulants. The Phase 1b n is small and it's only two-week data, but the EEG biomarker improvements give it more credibility than a symptom-score readout alone would.
Alkermes' orexin agonist shows potential to treat ADHD in early-stage trial ↗
Alkermes Reports First Positive Orexin-Agonist Data in ADHD With ALKS 7290 Phase 1b Trial
- Phase 1b study randomized 88 healthy volunteers and 50 adults with ADHD to ALKS 7290 20mg, 50mg, or placebo for 14 days, following a 2-week washout of existing ADHD medications.
- Participants began with a median AISRS score of ~39 (moderate-to-severe); by Day 14, reported median reductions were 14.0 points with 20mg and 19.0 points with 50mg, with the higher dose bringing scores into the mild range.
- Improvement was reported as early as Day 6 and spanned both inattentive and hyperactivity/impulsivity subscales; CGI-S scores fell by a median of 1 point (20mg) and 2 points (50mg).
- The drug was generally well tolerated across doses.
- This marks the first clinical evidence that an orexin 2 receptor agonist -- a drug class previously studied for rare sleep disorders like narcolepsy -- can improve ADHD symptoms.
- Alkermes describes the results as exploratory proof-of-concept rather than a powered efficacy readout, and says they support the dosing already chosen for an ongoing Phase 2 trial.
A genuinely new mechanism in ADHD is rare and commercially precious — this is the first clinical signal that orexin-2 agonism, a pathway built for narcolepsy, can move core ADHD symptoms, in a market still anchored by decades-old stimulant chemistry and underwhelming non-stimulants like atomoxetine and viloxazine. If it replicates, a non-stimulant with this magnitude of effect and no controlled-substance baggage would be a real wedge against stimulant-class incumbents. But read the fine print: only 50 ADHD patients, an unpowered Phase 1b that Alkermes itself calls exploratory proof-of-concept — sizeable AISRS drops here can evaporate once a properly powered, placebo-controlled Phase 2 reads out. For Alkermes, it's a second shot on goal for the orexin-2 franchise beyond narcolepsy (ALKS 2680), spreading platform risk into a much larger indication. Investors should treat this as a call option, not a catalyst, until Phase 2 data land.
Alkermes' orexin agonist shows potential to treat ADHD in early-stage trial ↗
New Benzimidazole-Tetrahydrofuran Series Delivers Potent, Selective NaV1.8 Inhibitor Lead for Pain
- NaV1.8 inhibition is a clinically validated non-opioid strategy for pain, with the marketed drug VX-548 (Journavx) serving as the benchmark; its metabolic pathways in humans and rats are well characterized.
- Researchers designed a new chemotype, 2-(2-benzimidazole)-substituted tetrahydrofurans, and applied structure-based optimization to circumvent VX-548's known metabolic liabilities while retaining nanomolar NaV1.8 potency and subtype selectivity.
- The resulting lead, compound 31, showed favorable oral bioavailability in rats, with plasma AUC more than 10-fold higher than VX-548, alongside potent in vivo analgesic efficacy.
- Pharmacokinetic behavior was consistent across species, with favorable profiles also seen in beagle dogs and cynomolgus monkeys.
- Compound 31 exhibited a favorable early safety profile, including no genotoxicity and weak hERG inhibition, supporting its status as a metabolically optimized preclinical lead for further evaluation.
Call this a metabolism play more than a new-target story. With VX-548's clearance liabilities already mapped in human and rat, swapping to a 2-benzimidazole-tetrahydrofuran scaffold reads as targeted scaffold-hopping around known soft spots rather than blind SAR exploration. That's the efficient way to run a fast-follower program: let the first approved drug's ADME data write your design brief. A >10x jump in rat AUC is the number that matters here — that's the difference between a compound needing frequent dosing with exposure gaps and one you can actually push into efficacy studies with margin. Clean hERG and no genotox flags this early derisks the biggest attrition risks before you've spent tox budget. The THF-benzimidazole core isn't exotic chemistry, nothing hard to scale — this looks like a real backup/second-gen candidate, not just a paper compound.
Large-Scale Virtual Screen Delivers Potent New TAAR1 Agonists for Schizophrenia
- TAAR1 is a G protein-coupled receptor pursued as a non-dopaminergic drug target for schizophrenia and antipsychotic therapy.
- A structure-based virtual screen docked about 65 million candidate molecules against an active-state model of TAAR1.
- Of 55 top-ranked hits tested experimentally, 14 showed genuine TAAR1 agonist activity, ranging from mid-nanomolar to micromolar potency.
- Hit optimization then yielded agonists with nanomolar potency, and cryo-EM structures confirmed the binding poses the docking had predicted.
- Three optimized agonists showed high brain exposure and potency described as exceeding that of ulotaront, a clinical-stage TAAR1 antipsychotic candidate.
- In mice, all three normalized amphetamine-induced disruption of pre-pulse inhibition, a schizophrenia-relevant behavioral measure, without causing catalepsy, a common antipsychotic side effect.
A 25% experimental hit rate (14/55) out of 65 million docked molecules is the number that jumps out — that's an unusually clean confirmation rate for an active-state GPCR model, and it's real validation for structure-based virtual screening on TAAR1, not just a docking-score exercise. Better still, cryo-EM backs up the predicted binding poses, so the model isn't just getting lucky on affinity. The pharmacology is the real prize: brain-penetrant, potency beating ulotaront, and no catalepsy in the PPI assay — that's the non-dopaminergic promise actually paying off, not just a slogan. Ulotaront is now the bar every TAAR1 agonist has to clear, and these three cleared it. Worth watching whether the SAR generalizes beyond these three chemotypes.
Structure based discovery of antipsychotic-like TAAR1 agonists ↗
GPR41 Agonism Curbs Endotoxemic Inflammation via Autophagy-Dependent NF-κB Suppression
- GPR41/FFAR3, a short-chain-fatty-acid-sensing GPCR, was tested as a target for dampening gut-derived endotoxemia in a macrophage model of endotoxin stress.
- The selective agonist AR420626 activated GPR41 and blunted downstream pro-inflammatory signaling, cutting output of nitric oxide, IL-6, MCP-1, and iNOS.
- This anti-inflammatory effect tracked to suppression of NF-κB signaling, the central pathway driving those mediators.
- Agonist treatment also boosted autophagic flux, marked by increased LC3-I-to-LC3-II conversion.
- Blocking autophagy pharmacologically erased AR420626's protective effect, indicating autophagy induction is mechanistically required rather than incidental to the anti-inflammatory action.
- Findings position GPR41 as a druggable node linking gut microbial metabolite sensing to control of systemic inflammation in metabolic endotoxemia.
AR420626 is doing its job as a chemical probe here, not auditioning as a drug — worth keeping that line bright. The autophagy-blockade rescue experiment is the real anchor: losing the phenotype when you knock out autophagy is exactly the epistasis data that justifies chasing GPR41 rather than filing it under "yet another anti-inflammatory hit." Selectivity is my first question mark — GPR41 sits right next to GPR43/FFAR2 in the SCFA-sensing GPCR family, sharing pocket architecture, so I'd want counter-screens before trusting any binding-mode hypothesis. Tractability-wise, class A GPCRs are historically good chemical space, but SCFA-mimetic ligands trend small and polar — solid fragment-to-lead starting points, not obviously oral-bioavailable as-is. Early hit-validation signal, not a lead series yet.
From Injections to Pills: A Blueprint for Oral GLP-1 Drugs
- This J. Med. Chem. perspective synthesizes lessons from four clinical-stage oral, nonpeptidic GLP-1 receptor agonists—danuglipron, lotiglipron, DA-302168S, and orforglipron—to outline a design blueprint for next-generation candidates.
- It frames a broader modality shift in metabolic disease therapeutics: from injectable peptide GLP-1RAs toward oral small molecules that could improve dosing convenience and patient acceptance.
- Orforglipron is highlighted as the first oral small-molecule GLP-1RA to reach approval, marking a proof-of-concept milestone for the class.
- The authors distill recurring structure-activity relationship tradeoffs among these first-generation candidates—balancing receptor potency, tolerability, and oral bioavailability—that shaped each program's clinical trajectory.
- Based on these comparisons, the review proposes design principles intended to guide future medicinal chemistry efforts toward improved oral GLP-1RAs.
GLP-1R's orthosteric pocket is deep and peptide-shaped — basically undruggable at drug-like MW/logP, so all four of these (danuglipron, lotiglipron, DA-302168S, orforglipron) work through allosteric or biased engagement rather than mimicking the peptide directly. That's the clever workaround, but it means potency, selectivity, and clean signaling bias have to be re-optimized empirically each time instead of inherited from orthosteric geometry. GI tolerability tracking with off-target signaling bias is still the recurring failure mode — lotiglipron's discontinuation is the cautionary tale here. No convergent scaffold yet: four programs, four distinct chemotypes, still bespoke SAR rather than a template anyone can reuse. Orforglipron's approval is proof-of-concept, not a formula. Expect the same peptide-to-oral-small-molecule chase to hit GIP and glucagon receptor programs next.