Your browser doesn't support javascript.
loading
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.
Afiliação
  • 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 em En | MEDLINE | ID: mdl-35684452
ABSTRACT
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.
Assuntos
Palavras-chave

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Plasmodium falciparum / Difosfotransferases / Antimaláricos Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Plasmodium falciparum / Difosfotransferases / Antimaláricos Idioma: En Ano de publicação: 2022 Tipo de documento: Article