LIGSITE: automatic and efficient detection of potential small molecule-binding sites in proteins

Hendlich, Manfred; Rippmann, Friedrich; Barnickel, Gerhard

doi:10.1016/s1093-3263(98)00002-3

Cited by 647 publications

(560 citation statements)

References 15 publications

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“…Our system relies on standard tools for computing the surfaces and other properties. For all examples in this paper, we use MSMS [29] to generate the molecular surface meshes, APBS [1] to compute electrostatic charge distributions, and an implementation of Ligsite [19] to identify putative binding pockets.…”

Section: Resultsmentioning

confidence: 99%

“…The output of region detectors, such as pocket finders, can also be displayed this way. Our system presently includes an an implementation of Ligsite [19] to identify potential pockets. The output of these detectors is noisy, so before constructing decals, small or low-confidence regions are removed to avoid clutter, and excessively large regions are also culled because they are usually errors from the pocket finder and are problematic for the exponential map creator.…”

Section: Using Decalsmentioning

confidence: 99%

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Molecular Surface Abstraction

Cipriano

Gleicher

2007

IEEE Trans. Visual. Comput. Graphics

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Abstract-In this paper we introduce a visualization technique that provides an abstracted view of the shape and spatio-physico-chemical properties of complex molecules. Unlike existing molecular viewing methods, our approach suppresses small details to facilitate rapid comprehension, yet marks the location of significant features so they remain visible. Our approach uses a combination of filters and mesh restructuring to generate a simplified representation that conveys the overall shape and spatio-physico-chemical properties (e.g. electrostatic charge). Surface markings are then used in the place of important removed details, as well as to supply additional information. These simplified representations are amenable to display using stylized rendering algorithms to further enhance comprehension. Our initial experience suggests that our approach is particularly useful in browsing collections of large molecules and in readily making comparisons between them.

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Section: Resultsmentioning

confidence: 99%

Section: Using Decalsmentioning

confidence: 99%

Molecular Surface Abstraction

Cipriano

Gleicher

2007

IEEE Trans. Visual. Comput. Graphics

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“…NMR and X-ray crystallography have been the primary analytical tools used to obtain detailed atomic-level characterization of protein-ligand interactions. Computational modeling using homology [35], docking or solvation [36], or grid [37] based methods is also playing a key role in identifying regions on proteins that may serve as a binding site as well as predicting what molecules will bind to that site. In this study, we have developed a high throughput time resolved limited proteolysis MALDI MS method to confirm doxorubicin's computationally predicted binding site to TetC [29].…”

Section: Resultsmentioning

confidence: 99%

Mass spectrometry and non-covalent protein-ligand complexes: Confirmation of binding sites and changes in tertiary structure

Shields

Oyeyemi

Lightstone

et al. 2003

J. Am. Soc. Mass Spectrom.

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An experimental approach is described for determining protein-small molecule non-covalent ligand binding sites and protein conformational changes induced by ligand binding. The methodology utilizes time resolved limited proteolysis and the high throughput analysis capability of MALDI TOF MS to determine the binding site in a tetanus toxin C-fragment (51 kDa)-doxorubicin (543 Da) non-covalent complex. Comparing relative ion abundances of peptides released from the time resolved limited proteolysis of tetanus toxin C-fragment (TetC) and the TetC-doxorubicin complex every 10 min from 10 to 120 min of digestion revealed that the binding of doxorubicin induced a significant change in surface topology of TetC. Four of the twenty-nine peptides observed by MALDI MS, including amino acids 351-360, 299 -304, 305-311 and 312-316, had a lower abundance in the TetC-doxorubicin complex relative to TetC from 10 to 100 min of digestion. A decrease in ion abundance suggests doxorubicin obstructs the access of the protease to one or both termini of these peptides, identifying doxorubicin binding site(s). Conversely, five peptide ions, including amino acids 335-350, 364 -375, 364 -376, 281-298, and 316 -328, all had a greater abundance in the digest of the complex, indicating an increase in accessibility to these sites. These five peptides flank regions of decreased ion abundance, suggesting that doxorubicin not only binds to the surface, but also induces a conformational change in TetC. (J Am Soc Mass Spectrom 2003, 14, 460 -470)

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“…Pocket-Finder or Q-site finder is a molecule-binding site prediction server based on a Ligsite algorithm (Hendlich et al, 1997). It works by scanning a probe radius 1.6Å along all gridlines of grid resolution 0.9Å surrounding the protein.…”

Section: Active Site Predictionmentioning

confidence: 99%

“…Grid points are defined to be part of a site when the probe is within range of protein atoms followed by free space followed by protein atoms. Grid points are only retained if they are defined to be part of a site at least five times (Hendlich et al, 1997). The different active sites in hGPR87 protein also predicted through CASTp server (Dundas et al, 2006) and compare their results with the pocket finder result.…”

Section: Active Site Predictionmentioning

confidence: 99%

Computational Analysis of the 3-D structure of Human GPR87 Protein: Implications for Structure-Based Drug Design

Rani

Nischal²,

Sahoo³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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The G-protein coupled receptor 87 (GPR87) is a recently discovered orphan GPCR which means that the search of their endogenous ligands has been a novel challenge. GPR87 has been shown to be overexpressed in squamous cell carcinomas (SCCs) or adenocarcinomas in lungs and bladder. The 3D structure of GPR87 was here modeled using two templates (2VT4 and 2ZIY) by a threading method. Functional assignment of GPR87 by SVM revealed that along with transporter activity, various novel functions were predicted. The 3D structure was further validated by comparison with structural features of the templates through Verify-3D, ProSA and ERRAT for determining correct stereochemical parameters. The resulting model was evaluated by Ramachandran plot and good 3D structure compatibility was evidenced by DOPE score. Molecular dynamics simulation and solvation of protein were studied through explicit spherical boundaries with a harmonic restraint membrane water system. A DRY-motif (Asp-Arg-Tyr sequence) was found at the end of transmembrane helix3, where GPCR binds and thus activation of signals is transduced. In a search for better inhibitors of GPR87, in silico modification of some substrate ligands was carried out to form polar interactions with Arg115 and Lys296. Thus, this study provides early insights into the structure of a major drug target for SCCs.

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LIGSITE: automatic and efficient detection of potential small molecule-binding sites in proteins

Cited by 647 publications

References 15 publications

Molecular Surface Abstraction

Molecular Surface Abstraction

Mass spectrometry and non-covalent protein-ligand complexes: Confirmation of binding sites and changes in tertiary structure

Computational Analysis of the 3-D structure of Human GPR87 Protein: Implications for Structure-Based Drug Design

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