ArticleProceedings of the National Academy of Sciences of the United States of America2016
Accelerated structure-based design of chemically diverse allosteric modulators of a muscarinic G protein-coupled receptor.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
46 citing papers in PubMed, 90 citations in OpenAlex.
- Targeting frizzled receptors (FZDs) for anti-tumor therapy: From orthosteric to allosteric inhibition.Acta pharmaceutica Sinica. B · 2026Review
- Visualizing agonist-induced M2 receptor activation regulated by aromatic ring dynamics.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Toward the Prediction of Binding Events in Very Flexible, Allosteric, Multidomain Proteins.Journal of chemical information and modeling · 2025Article
- Predicting binding events in very flexible, allosteric, multi-domain proteins.bioRxiv : the preprint server for biology · 2024Article
- Structure and dynamics in drug discovery.npj drug discovery · 2024Review
- The value of protein allostery in rational anticancer drug design: an update.Expert opinion on drug discovery · 2024Review
- G protein-coupled receptors (GPCRs): advances in structures, mechanisms, and drug discovery.Signal transduction and targeted therapy · 2024Review
- Capturing Differences in the Regulation of LRRK2 Dynamics and Conformational States by Small Molecule Kinase Inhibitors.ACS chemical biology · 2023Article
- Article
- Small molecule allosteric modulation of the adenosine AFrontiers in endocrinology · 2023Review
- Selective inhibitors of SARM1 targeting an allosteric cysteine in the autoregulatory ARM domain.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Molecular Simulations and Drug Discovery of Adenosine Receptors.Molecules (Basel, Switzerland) · 2022Review
- VARIDT 2.0: structural variability of drug transporter.Nucleic acids research · 2022Article
- The Impact of the Secondary Binding Pocket on the Pharmacology of Class A GPCRs.Frontiers in pharmacology · 2022Review
- Accelerating GPCR Drug Discovery With Conformation-Stabilizing VHHs.Frontiers in molecular biosciences · 2022Review
- Development of enhanced conformational sampling methods to probe the activation landscape of GPCRs.Advances in protein chemistry and structural biology · 2022Review
- Improving Structure-Based Virtual Screening with Ensemble Docking and Machine Learning.Journal of chemical information and modeling · 2021Article
- Conformational dynamics of androgen receptors bound to agonists and antagonists.Scientific reports · 2021Article
- Biomolecular Modeling and Simulation: A Prospering Multidisciplinary Field.Annual review of biophysics · 2021Article
- Biomolecular modeling thrives in the age of technology.Nature computational science · 2021Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Design of ligands that provide receptor selectivity has emerged as a new paradigm for drug discovery of G protein-coupled receptors, and may, for certain families of receptors, only be achieved via identification of chemically diverse allosteric modulators. Here, the extracellular vestibule of the M2 muscarinic acetylcholine receptor (mAChR) is targeted for structure-based design of allosteric modulators. Accelerated molecular dynamics (aMD) simulations were performed to construct structural ensembles that account for the receptor flexibility. Compounds obtained from the National Cancer Institute (NCI) were docked to the receptor ensembles. Retrospective docking of known ligands showed that combining aMD simulations with Glide induced fit docking (IFD) provided much-improved enrichment factors, compared with the Glide virtual screening workflow. Glide IFD was thus applied in receptor ensemble docking, and 38 top-ranked NCI compounds were selected for experimental testing. In [(3)H]N-methylscopolamine radioligand dissociation assays, approximately half of the 38 lead compounds altered the radioligand dissociation rate, a hallmark of allosteric behavior. In further competition binding experiments, we identified 12 compounds with affinity of ≤30 μM. With final functional experiments on six selected compounds, we confirmed four of them as new negative allosteric modulators (NAMs) and one as positive allosteric modulator of agonist-mediated response at the M2 mAChR. Two of the NAMs showed subtype selectivity without significant effect at the M1 and M3 mAChRs. This study demonstrates an unprecedented successful structure-based approach to identify chemically diverse and selective GPCR allosteric modulators with outstanding potential for further structure-activity relationship studies.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.