Virtual Screening Using Protein—Ligand Docking: Avoiding Artificial Enrichment.

Verdonk, Marcel L.; Berdini, Valério; Hartshorn, Michael J.; Mooij, Wijnand T. M.; Murray, Christopher W.; Taylor, Richard D.; Watson, Paul

doi:10.1002/chin.200430209

Cited by 150 publications

(284 citation statements)

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“…Substrate Screening-Compounds in the DrugBank list that had no literature link to sulfation and were predicted to be substrates by the SULT1A1 and 2A1 models were purchased from the Enzo drug library (28) and tested as substrates under following conditions: SULT (0.10 M dimer), substrate (10 M), Me 2 SO (Յ0.1%), 35 S-PAPS (3.0 M, 0.69 Ci/mmol), MgCl 2 (5.0 mM), KPO 4 (50 mM), pH 7.5, and T ϭ 25 Ϯ 2°C. The reactions were initiated by the addition of PAPS.…”

Section: Methodsmentioning

confidence: 99%

High Accuracy in Silico Sulfotransferase Models

Cook

Wang

Falany

et al. 2013

Journal of Biological Chemistry

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Background: Human sulfotransferases (SULTs) regulate the bioactivities of hundreds of compounds in vivo. Results:The in silico models of SULTs developed here proved remarkably accurate in identifying SULT substrates in a 1,455-compound library containing all FDA-approved drugs. Conclusion: Highly accurate in silico SULT models are now available. Significance: The elision of mechanism and modeling can produce remarkably accurate in silico tools for the study of biology.

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Section: Methodsmentioning

confidence: 99%

High Accuracy in Silico Sulfotransferase Models

Cook

Wang

Falany

et al. 2013

Journal of Biological Chemistry

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“…This opens up another field of potential future use for our methodology: By maximizing intraset nearestneighbor distances and minimizing the separation from the background in a simple reference descriptor space, benchmark data sets for ligand-based virtual screening can be designed, that prevent artificial enrichment as postulated by Verdonk et al 29 Current work is underway in our laboratory to provide a collection of such data sets.…”

Section: Resultsmentioning

confidence: 99%

“…it can deal with arbitrary distributions of benchmark data set and background. The target of this study is to complement the findings of Verdonk et al, 29 Bender et al, 12 and Good et al 31,32 on the validation of virtual screening methods by quantitative data.…”

Section: Introductionmentioning

confidence: 94%

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Impact of Benchmark Data Set Topology on the Validation of Virtual Screening Methods: Exploration and Quantification by Spatial Statistics

Rohrer

Baumann

2008

J. Chem. Inf. Model.

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A common finding of many reports evaluating ligand-based virtual screening methods is that validation results vary considerably with changing benchmark data sets. It is widely assumed that these data set specific effects are caused by the redundancy, self-similarity, and cluster structure inherent to those data sets. These phenomena manifest themselves in the data sets' representation in descriptor space, which is termed the data set topology. A methodology for the characterization of data set topology based on spatial statistics is introduced. The method is nonparametric and can deal with arbitrary distributions of descriptor values. With this methodology it is possible to associate differences in virtual screening performance on different data sets with differences in data set topology. Moreover, the better virtual screening performance of certain descriptors can be explained by their ability of representing the benchmark data sets by a more favorable topology. Finally it is shown, that the composition of some benchmark data sets causes topologies that lead to overoptimistic validation results even in very "simple" descriptor spaces. Spatial statistics analysis as proposed here facilitates the detection of such biased data sets and may provide a tool for the future design of unbiased benchmark data sets.

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“…The GROMAS57 field was modified in GROMACS to allow the program to recognize the spin-labeled cysteine as a canonical residue. Spin-labeled cysteines were inserted by replacing residues G29, E151, and K234; PAPS was positioned at the active site using GOLD (30)(31)(32); and the system was equilibrated using GROMACS (100-ps increments) to the following simulated condition: 298 K, 50 mM NaCl, and pH 7.4. Once equilibrated, EGCG was positioned randomly in a simulated box of water (52 × 52 × 52 Å) containing the spin-labeled SULT1A1·PAPS construct and then docked in GROMACS using the NMR distance constraints (Positioning EGCG and Results and Discussion).…”

Section: Methodsmentioning

confidence: 99%

The structure of the catechin-binding site of human sulfotransferase 1A1

Cook

Wang

Girvin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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We are just beginning to understand the allosteric regulation of the human cytosolic sulfotransferase (SULTs) family-13 disease-relevant enzymes that regulate the activities of hundreds, if not thousands, of signaling small molecules. SULT1A1, the predominant isoform in adult liver, harbors two noninteracting allosteric sites, each of which binds a different molecular family: the catechins (naturally occurring flavonols) and nonsteroidal antiinflammatory drugs (NSAIDs). Here, we present the structure of an SULT allosteric binding site-the catechin-binding site of SULT1A1 bound to epigallocatechin gallate (EGCG). The allosteric pocket resides in a dynamic region of the protein that enables EGCG to control opening and closure of the enzyme's active-site cap. Furthermore, the structure offers a molecular explanation for the isozyme specificity of EGCG, which is corroborated experimentally. The bindingsite structure was obtained without X-ray crystallography or multidimensional NMR. Instead, a SULT1A1 apoprotein structure was used to guide positioning of a small number of spin-labeled single-Cys mutants that coat the entire enzyme surface with a paramagnetic field of sufficient strength to determine its contribution to the bound ligand's transverse (T 2 ) relaxation from its 1D solution spectrum. EGCG protons were mapped to the protein surface by triangulation using the T 2 values to calculate their distances to a trio of spin-labeled Cys mutants. The final structure was obtained using distance-constrained molecular dynamics docking. This approach, which is readily extensible to other systems, is applicable over a wide range of ligand affinities, requires little protein, avoids the need for isotopically labeled protein, and has no protein molecular weight limitations.sulfotransferase | structure | NMR | allostery | catechin C ytosolic SULTs regulate disease-relevant process in virtually every tissue in the human body (1-5). This small family of broadspecificity enzymes regulates the activities of hundreds, perhaps thousands, of signaling small molecules (e.g., endogenous metabolites, drugs, and other xenobiotics) via regiospecific transfer of the sulfuryl moiety (-SO 3 ) from 3′-phosphoadenosine 5′-phosphosulfate (PAPS) to the hydroxyls and amines of acceptors (1, 6). Sulfonation often radically alters the interactions of a compound with its target and substantially enhances the target's solubility, transport, and clearance (1, 6, 7). Through these and other mechanisms, SULTs contribute in critical ways to maintaining signaling homeostasis and neutralizing toxins (6,8).Given their wide-ranging roles in regulating cellular processes, it is perhaps expected that SULTs would have evolved means of communicating with their environments-mechanisms that enable them to read and respond to the small-molecule composition of their "milieu." Early screening studies intimated that SULTs might be subject to small-molecule allosteric control (9, 10), and recent work confirms this (11). SULT1A1, the most abundant isoform in adult h...

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Virtual Screening Using Protein—Ligand Docking: Avoiding Artificial Enrichment.

Cited by 150 publications

References 1 publication

High Accuracy in Silico Sulfotransferase Models

High Accuracy in Silico Sulfotransferase Models

Impact of Benchmark Data Set Topology on the Validation of Virtual Screening Methods: Exploration and Quantification by Spatial Statistics

The structure of the catechin-binding site of human sulfotransferase 1A1

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