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Inhibition of Eimeria tenella CDK‐Related Kinase 2: From Target Identification to Lead Compounds
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| Zeitschriftentitel: | ChemMedChem |
|---|---|
| Personen und Körperschaften: | , , , , , , , , |
| In: | ChemMedChem, 5, 2010, 8, S. 1259-1271 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Wiley
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| Schlagwörter: |
| author_facet |
Engels, Kristin Beyer, Carsten Suárez Fernández, Maria L. Bender, Frank Gaßel, Michael Unden, Gottfried Marhöfer, Richard J. Mottram, Jeremy C. Selzer, Paul M. Engels, Kristin Beyer, Carsten Suárez Fernández, Maria L. Bender, Frank Gaßel, Michael Unden, Gottfried Marhöfer, Richard J. Mottram, Jeremy C. Selzer, Paul M. |
|---|---|
| author |
Engels, Kristin Beyer, Carsten Suárez Fernández, Maria L. Bender, Frank Gaßel, Michael Unden, Gottfried Marhöfer, Richard J. Mottram, Jeremy C. Selzer, Paul M. |
| spellingShingle |
Engels, Kristin Beyer, Carsten Suárez Fernández, Maria L. Bender, Frank Gaßel, Michael Unden, Gottfried Marhöfer, Richard J. Mottram, Jeremy C. Selzer, Paul M. ChemMedChem Inhibition of Eimeria tenella CDK‐Related Kinase 2: From Target Identification to Lead Compounds Organic Chemistry General Pharmacology, Toxicology and Pharmaceutics Molecular Medicine Drug Discovery Biochemistry Pharmacology |
| author_sort |
engels, kristin |
| spelling |
Engels, Kristin Beyer, Carsten Suárez Fernández, Maria L. Bender, Frank Gaßel, Michael Unden, Gottfried Marhöfer, Richard J. Mottram, Jeremy C. Selzer, Paul M. 1860-7179 1860-7187 Wiley Organic Chemistry General Pharmacology, Toxicology and Pharmaceutics Molecular Medicine Drug Discovery Biochemistry Pharmacology http://dx.doi.org/10.1002/cmdc.201000157 <jats:title>Abstract</jats:title><jats:p>Apicomplexan parasites encompass several human‐ and animal‐pathogenic protozoans such as <jats:italic>Plasmodium falciparum</jats:italic>, <jats:italic>Toxoplasma gondii</jats:italic>, and <jats:italic>Eimeria tenella</jats:italic>. <jats:italic>E. tenella</jats:italic> causes coccidiosis, a disease that afflicts chickens, leading to tremendous economic losses to the global poultry industry. The considerable increase in drug resistance makes it necessary to develop new therapeutic strategies against this parasite. Cyclin‐dependent kinases (CDKs) are key molecules in cell‐cycle regulation and are therefore prominent target proteins in parasitic diseases. Bioinformatics analysis revealed four potential CDK‐like proteins, of which one—<jats:italic>E. tenella</jats:italic> CDK‐related kinase 2 (EtCRK2)—has already been characterized by gene cloning and expression.<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#bib1">1</jats:ext-link> By using the CDK‐specific inhibitor flavopiridol in EtCRK2 enzyme assays and schizont maturation assays (SMA), we could chemically validate CDK‐like proteins as potential drug targets. An X‐ray crystal structure of human CDK2 (HsCDK2) served as a template to build protein models of EtCRK2 by comparative homology modeling. Structural differences in the ATP binding site between EtCRK2 and HsCDK2, as well as chicken CDK3, were addressed for the optimization of selective ATP‐competitive 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 for development as EtCRK2 inhibitors.</jats:p> Inhibition of <i>Eimeria tenella</i> CDK‐Related Kinase 2: From Target Identification to Lead Compounds ChemMedChem |
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| title |
Inhibition of Eimeria tenella CDK‐Related Kinase 2: From Target Identification to Lead Compounds |
| title_unstemmed |
Inhibition of Eimeria tenella CDK‐Related Kinase 2: From Target Identification to Lead Compounds |
| title_full |
Inhibition of Eimeria tenella CDK‐Related Kinase 2: From Target Identification to Lead Compounds |
| title_fullStr |
Inhibition of Eimeria tenella CDK‐Related Kinase 2: From Target Identification to Lead Compounds |
| title_full_unstemmed |
Inhibition of Eimeria tenella CDK‐Related Kinase 2: From Target Identification to Lead Compounds |
| title_short |
Inhibition of Eimeria tenella CDK‐Related Kinase 2: From Target Identification to Lead Compounds |
| title_sort |
inhibition of <i>eimeria tenella</i> cdk‐related kinase 2: from target identification to lead compounds |
| topic |
Organic Chemistry General Pharmacology, Toxicology and Pharmaceutics Molecular Medicine Drug Discovery Biochemistry Pharmacology |
| url |
http://dx.doi.org/10.1002/cmdc.201000157 |
| publishDate |
2010 |
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1259-1271 |
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<jats:title>Abstract</jats:title><jats:p>Apicomplexan parasites encompass several human‐ and animal‐pathogenic protozoans such as <jats:italic>Plasmodium falciparum</jats:italic>, <jats:italic>Toxoplasma gondii</jats:italic>, and <jats:italic>Eimeria tenella</jats:italic>. <jats:italic>E. tenella</jats:italic> causes coccidiosis, a disease that afflicts chickens, leading to tremendous economic losses to the global poultry industry. The considerable increase in drug resistance makes it necessary to develop new therapeutic strategies against this parasite. Cyclin‐dependent kinases (CDKs) are key molecules in cell‐cycle regulation and are therefore prominent target proteins in parasitic diseases. Bioinformatics analysis revealed four potential CDK‐like proteins, of which one—<jats:italic>E. tenella</jats:italic> CDK‐related kinase 2 (EtCRK2)—has already been characterized by gene cloning and expression.<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#bib1">1</jats:ext-link> By using the CDK‐specific inhibitor flavopiridol in EtCRK2 enzyme assays and schizont maturation assays (SMA), we could chemically validate CDK‐like proteins as potential drug targets. An X‐ray crystal structure of human CDK2 (HsCDK2) served as a template to build protein models of EtCRK2 by comparative homology modeling. Structural differences in the ATP binding site between EtCRK2 and HsCDK2, as well as chicken CDK3, were addressed for the optimization of selective ATP‐competitive 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 for development as EtCRK2 inhibitors.</jats:p> |
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| author | Engels, Kristin, Beyer, Carsten, Suárez Fernández, Maria L., Bender, Frank, Gaßel, Michael, Unden, Gottfried, Marhöfer, Richard J., Mottram, Jeremy C., Selzer, Paul M. |
| author_facet | Engels, Kristin, Beyer, Carsten, Suárez Fernández, Maria L., Bender, Frank, Gaßel, Michael, Unden, Gottfried, Marhöfer, Richard J., Mottram, Jeremy C., Selzer, Paul M., Engels, Kristin, Beyer, Carsten, Suárez Fernández, Maria L., Bender, Frank, Gaßel, Michael, Unden, Gottfried, Marhöfer, Richard J., Mottram, Jeremy C., Selzer, Paul M. |
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| description | <jats:title>Abstract</jats:title><jats:p>Apicomplexan parasites encompass several human‐ and animal‐pathogenic protozoans such as <jats:italic>Plasmodium falciparum</jats:italic>, <jats:italic>Toxoplasma gondii</jats:italic>, and <jats:italic>Eimeria tenella</jats:italic>. <jats:italic>E. tenella</jats:italic> causes coccidiosis, a disease that afflicts chickens, leading to tremendous economic losses to the global poultry industry. The considerable increase in drug resistance makes it necessary to develop new therapeutic strategies against this parasite. Cyclin‐dependent kinases (CDKs) are key molecules in cell‐cycle regulation and are therefore prominent target proteins in parasitic diseases. Bioinformatics analysis revealed four potential CDK‐like proteins, of which one—<jats:italic>E. tenella</jats:italic> CDK‐related kinase 2 (EtCRK2)—has already been characterized by gene cloning and expression.<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#bib1">1</jats:ext-link> By using the CDK‐specific inhibitor flavopiridol in EtCRK2 enzyme assays and schizont maturation assays (SMA), we could chemically validate CDK‐like proteins as potential drug targets. An X‐ray crystal structure of human CDK2 (HsCDK2) served as a template to build protein models of EtCRK2 by comparative homology modeling. Structural differences in the ATP binding site between EtCRK2 and HsCDK2, as well as chicken CDK3, were addressed for the optimization of selective ATP‐competitive 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 for development as EtCRK2 inhibitors.</jats:p> |
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| spelling | Engels, Kristin Beyer, Carsten Suárez Fernández, Maria L. Bender, Frank Gaßel, Michael Unden, Gottfried Marhöfer, Richard J. Mottram, Jeremy C. Selzer, Paul M. 1860-7179 1860-7187 Wiley Organic Chemistry General Pharmacology, Toxicology and Pharmaceutics Molecular Medicine Drug Discovery Biochemistry Pharmacology http://dx.doi.org/10.1002/cmdc.201000157 <jats:title>Abstract</jats:title><jats:p>Apicomplexan parasites encompass several human‐ and animal‐pathogenic protozoans such as <jats:italic>Plasmodium falciparum</jats:italic>, <jats:italic>Toxoplasma gondii</jats:italic>, and <jats:italic>Eimeria tenella</jats:italic>. <jats:italic>E. tenella</jats:italic> causes coccidiosis, a disease that afflicts chickens, leading to tremendous economic losses to the global poultry industry. The considerable increase in drug resistance makes it necessary to develop new therapeutic strategies against this parasite. Cyclin‐dependent kinases (CDKs) are key molecules in cell‐cycle regulation and are therefore prominent target proteins in parasitic diseases. Bioinformatics analysis revealed four potential CDK‐like proteins, of which one—<jats:italic>E. tenella</jats:italic> CDK‐related kinase 2 (EtCRK2)—has already been characterized by gene cloning and expression.<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#bib1">1</jats:ext-link> By using the CDK‐specific inhibitor flavopiridol in EtCRK2 enzyme assays and schizont maturation assays (SMA), we could chemically validate CDK‐like proteins as potential drug targets. An X‐ray crystal structure of human CDK2 (HsCDK2) served as a template to build protein models of EtCRK2 by comparative homology modeling. Structural differences in the ATP binding site between EtCRK2 and HsCDK2, as well as chicken CDK3, were addressed for the optimization of selective ATP‐competitive 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 for development as EtCRK2 inhibitors.</jats:p> Inhibition of <i>Eimeria tenella</i> CDK‐Related Kinase 2: From Target Identification to Lead Compounds ChemMedChem |
| spellingShingle | Engels, Kristin, Beyer, Carsten, Suárez Fernández, Maria L., Bender, Frank, Gaßel, Michael, Unden, Gottfried, Marhöfer, Richard J., Mottram, Jeremy C., Selzer, Paul M., ChemMedChem, Inhibition of Eimeria tenella CDK‐Related Kinase 2: From Target Identification to Lead Compounds, Organic Chemistry, General Pharmacology, Toxicology and Pharmaceutics, Molecular Medicine, Drug Discovery, Biochemistry, Pharmacology |
| title | Inhibition of Eimeria tenella CDK‐Related Kinase 2: From Target Identification to Lead Compounds |
| title_full | Inhibition of Eimeria tenella CDK‐Related Kinase 2: From Target Identification to Lead Compounds |
| title_fullStr | Inhibition of Eimeria tenella CDK‐Related Kinase 2: From Target Identification to Lead Compounds |
| title_full_unstemmed | Inhibition of Eimeria tenella CDK‐Related Kinase 2: From Target Identification to Lead Compounds |
| title_short | Inhibition of Eimeria tenella CDK‐Related Kinase 2: From Target Identification to Lead Compounds |
| title_sort | inhibition of <i>eimeria tenella</i> cdk‐related kinase 2: from target identification to lead compounds |
| title_unstemmed | Inhibition of Eimeria tenella CDK‐Related Kinase 2: From Target Identification to Lead Compounds |
| topic | Organic Chemistry, General Pharmacology, Toxicology and Pharmaceutics, Molecular Medicine, Drug Discovery, Biochemistry, Pharmacology |
| url | http://dx.doi.org/10.1002/cmdc.201000157 |