Virtual Screening for Submicromolar Leads of tRNA-guanine Transglycosylase Based on a New Unexpected Binding Mode Detected by Crystal Structure Analysis

Brenk, Ruth; Nærum, Lars; Grädler, Ulrich; Gerber, Hans Dieter; Garcia, George A.; Reuter, Klaus; Stubbs, Milton T.; Klebe, G.

doi:10.1021/jm0209937

Cited by 101 publications

(107 citation statements)

References 43 publications

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“…Numerous successful applications of this strategy have been reported in the literature. [15][16][17][18][19] In this study, we have shown that different virtual-screening methods generally seem to provide complementary hit lists of actives. Moreover, it is known that ligand-based virtual screenings based on different reference ligands or docking into different protein structures [46] provide different sets of actives.…”

Section: Application Of Virtual-screening Hypotheses Derived From Mulmentioning

confidence: 89%

Comparison of Structure‐ and Ligand‐Based Virtual Screening Protocols Considering Hit List Complementarity and Enrichment Factors

Krüger¹,

Evers

2009

ChemMedChem

119

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Structure- and ligand-based virtual-screening methods (docking, 2D- and 3D-similarity searching) were analysed for their effectiveness in virtual screening against four different targets: angiotensin-converting enzyme (ACE), cyclooxygenase 2 (COX-2), thrombin and human immunodeficiency virus 1 (HIV-1) protease. The relative performance of the tools was compared by examining their ability to recognise known active compounds from a set of actives and nonactives. Furthermore, we investigated whether the application of different virtual-screening methods in parallel provides complementary or redundant hit lists. Docking was performed with GOLD, Glide, FlexX and Surflex. The obtained docking poses were rescored by using nine different scoring functions in addition to the scoring functions implemented as objective functions in the docking algorithms. Ligand-based virtual screening was done with ROCS (3D-similarity searching), Feature Trees and Scitegic Functional Fingerprints (2D-similarity searching). The results show that structure- and ligand-based virtual-screening methods provide comparable enrichments in detecting active compounds. Interestingly, the hit lists that are obtained from different virtual-screening methods are generally highly complementary. These results suggest that a parallel application of different structure- and ligand-based virtual-screening methods increases the chance of identifying more (and more diverse) active compounds from a virtual-screening campaign.

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Section: Application Of Virtual-screening Hypotheses Derived From Mulmentioning

confidence: 89%

Comparison of Structure‐ and Ligand‐Based Virtual Screening Protocols Considering Hit List Complementarity and Enrichment Factors

Krüger¹,

Evers

2009

ChemMedChem

119

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“…Docking screens compound libraries for molecules that physically complement protein-binding sites. The technique has been used to discover new ligands in the ''lead-like'' (typically Յ350 Da) or drug-like ranges (typically Յ500 Da) (12,13); some of these new ligands have been determined in complex with their targets by crystallography in geometries consistent with the docking predictions (14)(15)(16)(17). Docking has also been used to prioritize molecules for fragment-based screens for several targets (5,(18)(19)(20).…”

mentioning

confidence: 99%

Docking for fragment inhibitors of AmpC β-lactamase

Teotico

Babaoglu

Rocklin

et al. 2009

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

103

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Fragment screens for new ligands have had wide success, notwithstanding their constraint to libraries of 1,000 -10,000 molecules. Larger libraries would be addressable were molecular docking reliable for fragment screens, but this has not been widely accepted. To investigate docking's ability to prioritize fragments, a library of >137,000 such molecules were docked against the structure of ␤-lactamase. Forty-eight fragments highly ranked by docking were acquired and tested; 23 had Ki values ranging from 0.7 to 9.2 mM. X-ray crystal structures of the enzyme-bound complexes were determined for 8 of the fragments. For 4, the correspondence between the predicted and experimental structures was high (RMSD between 1.2 and 1.4 Å), whereas for another 2, the fidelity was lower but retained most key interactions (RMSD 2.4 -2.6 Å). Two of the 8 fragments adopted very different poses in the active site owing to enzyme conformational changes. The 48% hit rate of the fragment docking compares very favorably with ''lead-like'' docking and high-throughput screening against the same enzyme. To understand this, we investigated the occurrence of the fragment scaffolds among larger, lead-like molecules. Approximately 1% of commercially available fragments contain these inhibitors whereas only 10 ؊7 % of lead-like molecules do. This suggests that many more chemotypes and combinations of chemotypes are present among fragments than are available among lead-like molecules, contributing to the higher hit rates. The ability of docking to prioritize these fragments suggests that the technique can be used to exploit the better chemotype coverage that exists at the fragment level.crystallography ͉ drug design ͉ hit rates ͉ chemical space

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“…Recently, the tgt gene has been implicated in the virulence of Shigella flexneri, a dysentery-causing bacterium (9,10). Given this, TGT presents itself as a potential novel antibiotic target (11,12).…”

mentioning

confidence: 99%

An Essential Role for Aspartate 264 in Catalysis by tRNA-Guanine Transglycosylase from Escherichia coli

Kittendorf

Sgraja

Reuter

et al. 2003

Journal of Biological Chemistry

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Virtual Screening for Submicromolar Leads of tRNA-guanine Transglycosylase Based on a New Unexpected Binding Mode Detected by Crystal Structure Analysis

Cited by 101 publications

References 43 publications

Comparison of Structure‐ and Ligand‐Based Virtual Screening Protocols Considering Hit List Complementarity and Enrichment Factors

Comparison of Structure‐ and Ligand‐Based Virtual Screening Protocols Considering Hit List Complementarity and Enrichment Factors

Docking for fragment inhibitors of AmpC β-lactamase

An Essential Role for Aspartate 264 in Catalysis by tRNA-Guanine Transglycosylase from Escherichia coli

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