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Assay Development and Identification of the First Plasmodium falciparum 7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase Inhibitors.
Hoarau, Marie; Suwanakitti, Nattida; Varatthan, Thaveechai; Thiabma, Ratthiya; Rattanajak, Roonglawan; Charoensetakul, Netnapa; Redman, Emily K; Khotavivattana, Tanatorn; Vilaivan, Tirayut; Yuthavong, Yongyuth; Kamchonwongpaisan, Sumalee.
Afiliación
  • Hoarau M; National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani 12120, Thailand.
  • Suwanakitti N; National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani 12120, Thailand.
  • Varatthan T; National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani 12120, Thailand.
  • Thiabma R; National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani 12120, Thailand.
  • Rattanajak R; National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani 12120, Thailand.
  • Charoensetakul N; National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani 12120, Thailand.
  • Redman EK; Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
  • Khotavivattana T; Center of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
  • Vilaivan T; Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
  • Yuthavong Y; National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani 12120, Thailand.
  • Kamchonwongpaisan S; National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani 12120, Thailand.
Molecules ; 27(11)2022 May 30.
Article en En | MEDLINE | ID: mdl-35684452
In the fight towards eradication of malaria, identifying compounds active against new drug targets constitutes a key approach. Plasmodium falciparum 7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase (PfHPPK) has been advanced as a promising target, as being part of the parasite essential folate biosynthesis pathway while having no orthologue in the human genome. However, no drug discovery efforts have been reported on this enzyme. In this study, we conducted a three-step screening of our in-house antifolate library against PfHPPK using a newly designed PfHPPK-GFP protein construct. Combining virtual screening, differential scanning fluorimetry and enzymatic assay, we identified 14 compounds active against PfHPPK. Compounds' binding modes were investigated by molecular docking, suggesting competitive binding with the HMDP substrate. Cytotoxicity and in vitro ADME properties of hit compounds were also assessed, showing good metabolic stability and low toxicity. The most active compounds displayed low micromolar IC50 against drug-resistant parasites. The reported hit compounds constitute a good starting point for inhibitor development against PfHPPK, as an alternative approach to tackle the malaria parasite.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Plasmodium falciparum / Difosfotransferasas / Antimaláricos Tipo de estudio: Diagnostic_studies Límite: Humans Idioma: En Revista: Molecules Asunto de la revista: BIOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Tailandia Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Plasmodium falciparum / Difosfotransferasas / Antimaláricos Tipo de estudio: Diagnostic_studies Límite: Humans Idioma: En Revista: Molecules Asunto de la revista: BIOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Tailandia Pais de publicación: Suiza