Searching New Antiparasitics in Virtual Space

Oellien, Frank; Engels, Kristin; Cramer, Jörg; Marhöfer, Richard J.; Kern, Christopher; Selzer, Paul M.

doi:10.1002/9783527626816.ch17

Cited by 2 publications

(1 citation statement)

References 26 publications

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“…The virtual screening used in this study was set up in a similar way to former studies. [40-42] We employed a customized common multi-step filtering protocol [40-43] as depicted in Figure 4. It consisted of a 3D pharmacophore filtering step, the docking and scoring procedure, and a post-processing for docked ligands.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Eimeria tenella CDK‐Related Kinase 2: From Target Identification to Lead Compounds

Engels

Beyer

Fernández³

et al. 2010

ChemMedChem

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Apicomplexan parasites encompass several human-pathogenic as well as animal-pathogenic protozoans like Plasmodium falciparum, Toxoplasma gondii, and Eimeria tenella. E. tenella is the causative agent of coccidiosis a disease of chickens, which causes tremendous economic losses to the world poultry industry. Considerable increase of drug resistance makes it necessary to develop and pursue new therapeutic strategies. Cyclin-dependent kinases (CDKs) are key molecules in the regulation of the cell cycle and are therefore prominent target proteins in parasitic diseases. Bioinformatic analysis revealed four potential CDK-like proteins of which one -E. tenella CDKrelated kinase 2 (EtCRK2) -is already cloned, expressed and characterized. [1] Using the CDK specific inhibitor Flavopiridol in EtCRK2 enzyme assays and schizont maturation assays we could chemically validate CDK-like proteins as potential drug targets. An X-ray crystal structure of human CDK2 (HsCDK2) served as template to built protein models of EtCRK2 by comparative homology modeling. Structural differences in the ATP-binding site between EtCRK2 and HsCDK2 as well as chicken CDK3 have been addressed for the optimization of selective ATPcompetitive inhibitors. Virtual screening and "wet-bench" high throughput screening campaigns on large compound libraries resulted in an initial set of hit compounds. These compounds were further analyzed and characterized leading to a set of four promising lead compounds inhibiting EtCRK2.

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