ArticleChemical biology & drug design2010
Mapping the druggable allosteric space of G-protein coupled receptors: a fragment-based molecular dynamics approach.
Article in Chemical biology & drug design, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 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
57 citing papers in PubMed.
- A non-canonical mechanism of GPCR activation.Nature communications · 2024Article
- Article
- Know your molecule: pharmacological characterization of drug candidates to enhance efficacy and reduce late-stage attrition.Nature reviews. Drug discovery · 2024Review
- Toward physics-based precision medicine: Exploiting protein dynamics to design new therapeutics and interpret variants.Protein science : a publication of the Protein Society · 2024Review
- Activity Map and Transition Pathways of G Protein-Coupled Receptor Revealed by Machine Learning.Journal of chemical information and modeling · 2023Article
- Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands.International journal of molecular sciences · 2023Review
- Predicting locations of cryptic pockets from single protein structures using the PocketMiner graph neural network.Nature communications · 2023Article
- Conservation of Allosteric Ligand Binding Sites in G-Protein Coupled Receptors.Journal of chemical information and modeling · 2022Article
- An Evolutionary Conservation and Druggability Analysis of Enzymes Belonging to the Bacterial Shikimate Pathway.Antibiotics (Basel, Switzerland) · 2022Article
- How does a small molecule bind at a cryptic binding site?PLoS computational biology · 2022Article
- PyLipID: A Python Package for Analysis of Protein-Lipid Interactions from Molecular Dynamics Simulations.Journal of chemical theory and computation · 2022Article
- Molecular dynamics simulations reveal the selectivity mechanism of structurally similar agonists to TLR7 and TLR8.PloS one · 2022Article
- In Silico Identification of Potential Druggable Binding Sites on CIN85 SH3 Domain.International journal of molecular sciences · 2021Article
- Allosteric Modulator Leads Hiding in Plain Site: Developing Peptide and Peptidomimetics as GPCR Allosteric Modulators.Frontiers in chemistry · 2021Review
- Computational insights into the molecular mechanisms of differentiated allosteric modulation at the mu opioid receptor by structurally similar bitopic modulators.Journal of computer-aided molecular design · 2020Article
- Pharmmaker: Pharmacophore modeling and hit identification based on druggability simulations.Protein science : a publication of the Protein Society · 2020Article
- Mechanism of βScience (New York, N.Y.) · 2019Article
- Analysis of tractable allosteric sites in G protein-coupled receptors.Scientific reports · 2019Article
- Advanced Methods for Accessing Protein Shape-Shifting Present New Therapeutic Opportunities.Trends in biochemical sciences · 2019Review
- Ensemble docking to difficult targets in early-stage drug discovery: Methodology and application to fibroblast growth factor 23.Chemical biology & drug design · 2018Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
2 authors.
Funding
Abstract
To address the problem of specificity in G-protein coupled receptor (GPCR) drug discovery, there has been tremendous recent interest in allosteric drugs that bind at sites topographically distinct from the orthosteric site. Unfortunately, structure-based drug design of allosteric GPCR ligands has been frustrated by the paucity of structural data for allosteric binding sites, making a strong case for predictive computational methods. In this work, we map the surfaces of the beta1 (beta1AR) and beta2 (beta2AR) adrenergic receptor structures to detect a series of five potentially druggable allosteric sites. We employ the FTMAP algorithm to identify 'hot spots' with affinity for a variety of organic probe molecules corresponding to drug fragments. Our work is distinguished by an ensemble-based approach, whereby we map diverse receptor conformations taken from molecular dynamics (MD) simulations totaling approximately 0.5 micros. Our results reveal distinct pockets formed at both solvent-exposed and lipid-exposed cavities, which we interpret in light of experimental data and which may constitute novel targets for GPCR drug discovery. This mapping data can now serve to drive a combination of fragment-based and virtual screening approaches for the discovery of small molecules that bind at these sites and which may offer highly selective therapies.
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.