143 research outputs found
In silico design of novel probes for the atypical opioid receptor MRGPRX2
The primate-exclusive MRGPRX2 G protein-coupled receptor (GPCR) has been suggested to modulate pain and itch. Despite putative peptide and small molecule MRGPRX2 agonists, selective nanomolar potency probes have not yet been reported. To identify a MRGPRX2 probe, we first screened 5,695 small molecules and found many opioid compounds activated MRGPRX2, including (−)- and (+)-morphine, hydrocodone, sinomenine, dextromethorphan and the prodynorphin-derived peptides, dynorphin A, dynorphin B, and α- and β-neoendorphin. We used these to select for mutagenesis-validated homology models and docked almost 4 million small molecules. From this docking, we predicted ZINC-3573, which represents a potent MRGPRX2-selective agonist, showing little activity against 315 other GPCRs and 97 representative kinases, and an essentially inactive enantiomer. ZINC-3573 activates endogenous MRGPRX2 in a human mast cell line inducing degranulation and calcium release. MRGPRX2 is a unique atypical opioid-like receptor important for modulating mast cell degranulation, which can now be specifically modulated with ZINC-3573
Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment
The community-wide GPCR Dock assessment is conducted to evaluate the status of molecular modeling and ligand docking for human G protein-coupled receptors. The present round of the assessment was based on the recent structures of dopamine D3 and CXCR4 chemokine receptors bound to small molecule antagonists and CXCR4 with a synthetic cyclopeptide. Thirty-five groups submitted their receptor-ligand complex structure predictions prior to the release of the crystallographic coordinates. With closely related homology modeling templates, as for dopamine D3 receptor, and with incorporation of biochemical and QSAR data, modern computational techniques predicted complex details with accuracy approaching experimental. In contrast, CXCR4 complexes that had less-characterized interactions and only distant homology to the known GPCR structures still remained very challenging. The assessment results provide guidance for modeling and crystallographic communities in method development and target selection for further expansion of the structural coverage of the GPCR universe. © 2011 Elsevier Ltd. All rights reserved
Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone
Dopamine is a neurotransmitter that has been implicated in processes as diverse as reward, addiction, control of coordinated movement, metabolism and hormonal secretion. Correspondingly, dysregulation of the dopaminergic system has been implicated in diseases such as schizophrenia, Parkinson's disease, depression, attention deficit hyperactivity disorder, and nausea and vomiting. The actions of dopamine are mediated by a family of five G-protein-coupled receptors. The D2 dopamine receptor (DRD2) is the primary target for both typical and atypical antipsychotic drugs, and for drugs used to treat Parkinson's disease. Unfortunately, many drugs that target DRD2 cause serious and potentially life-threatening side effects due to promiscuous activities against related receptors. Accordingly, a molecular understanding of the structure and function of DRD2 could provide a template for the design of safer and more effective medications. Here we report the crystal structure of DRD2 in complex with the widely prescribed atypical antipsychotic drug risperidone. The DRD2-risperidone structure reveals an unexpected mode of antipsychotic drug binding to dopamine receptors, and highlights structural determinants that are essential for the actions of risperidone and related drugs at DRD2. © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved
Directory of Useful Decoys, Enhanced (DUD-E): Better Ligands and Decoys for Better Benchmarking
A key metric to assess molecular docking remains ligand
enrichment
against challenging decoys. Whereas the directory of useful decoys
(DUD) has been widely used, clear areas for optimization have emerged.
Here we describe an improved benchmarking set that includes more diverse
targets such as GPCRs and ion channels, totaling 102 proteins with
22886 clustered ligands drawn from ChEMBL, each with 50 property-matched
decoys drawn from ZINC. To ensure chemotype diversity, we cluster
each target’s ligands by their Bemis–Murcko atomic frameworks.
We add net charge to the matched physicochemical properties and include
only the most dissimilar decoys, by topology, from the ligands. An
online automated tool (http://decoys.docking.org) generates
these improved matched decoys for user-supplied ligands. We test this
data set by docking all 102 targets, using the results to improve
the balance between ligand desolvation and electrostatics in DOCK
3.6. The complete DUD-E benchmarking set is freely available at http://dude.docking.org
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Automated docking screens: a feasibility study.
Molecular docking is the most practical approach to leverage protein structure for ligand discovery, but the technique retains important liabilities that make it challenging to deploy on a large scale. We have therefore created an expert system, DOCK Blaster, to investigate the feasibility of full automation. The method requires a PDB code, sometimes with a ligand structure, and from that alone can launch a full screen of large libraries. A critical feature is self-assessment, which estimates the anticipated reliability of the automated screening results using pose fidelity and enrichment. Against common benchmarks, DOCK Blaster recapitulates the crystal ligand pose within 2 A rmsd 50-60% of the time; inferior to an expert, but respectrable. Half the time the ligand also ranked among the top 5% of 100 physically matched decoys chosen on the fly. Further tests were undertaken culminating in a study of 7755 eligible PDB structures. In 1398 cases, the redocked ligand ranked in the top 5% of 100 property-matched decoys while also posing within 2 A rmsd, suggesting that unsupervised prospective docking is viable. DOCK Blaster is available at http://blaster.docking.org
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Predicted Biological Activity of Purchasable Chemical Space
Whereas
400 million distinct compounds are now purchasable within
the span of a few weeks, the biological activities of most are unknown.
To facilitate access to new chemistry for biology, we have combined
the Similarity Ensemble Approach (SEA) with the maximum Tanimoto similarity
to the nearest bioactive to predict activity for every commercially
available molecule in ZINC. This method, which we label SEA+TC, outperforms
both SEA and a naïve-Bayesian classifier via predictive performance
on a 5-fold cross-validation of ChEMBL’s bioactivity data set
(version 21). Using this method, predictions for over 40% of compounds
(>160 million) have either high significance (pSEA ≥ 40),
high
similarity (ECFP4MaxTc ≥ 0.4), or both, for one or more of
1382 targets well described by ligands in the literature. Using a
further 1347 less-well-described targets, we predict activities for
an additional 11 million compounds. To gauge whether these predictions
are sensible, we investigate 75 predictions for 50 drugs lacking a
binding affinity annotation in ChEMBL. The 535 million predictions
for over 171 million compounds at 2629 targets are linked to purchasing
information and evidence to support each prediction and are freely
available via https://zinc15.docking.org and https://files.docking.org
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