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Identification of potential inhibitors of casein kinase 2 alpha of Plasmodium falciparum with potent in vitro activity.
Tomaz, Kaira C P; Tavella, Tatyana A; Borba, Joyce V B; Salazar-Alvarez, Luis C; Levandoski, João E; Mottin, Melina; Sousa, Bruna K P; Moreira-Filho, José T; Almeida, Vitor M; Clementino, Leandro C; Bourgard, Catarina; Massirer, Katlin B; Couñago, Rafael M; Andrade, Carolina H; Sunnerhagen, Per; Bilsland, Elizabeth; Cassiano, Gustavo C; Costa, Fabio T M.
Afiliación
  • Tomaz KCP; Laboratory of Tropical Diseases (LDT), Institute of Biology, University of Campinas , Campinas, Brazil.
  • Tavella TA; Laboratory of Tropical Diseases (LDT), Institute of Biology, University of Campinas , Campinas, Brazil.
  • Borba JVB; Laboratory of Tropical Diseases (LDT), Institute of Biology, University of Campinas , Campinas, Brazil.
  • Salazar-Alvarez LC; Laboratory of Molecular Modeling and Drug Design (LabMol), Faculty of Pharmacy, Universidade Federal de Goiás (UFG) , Goiânia, Brazil.
  • Levandoski JE; Laboratory of Tropical Diseases (LDT), Institute of Biology, University of Campinas , Campinas, Brazil.
  • Mottin M; Department of Materials and Bioprocesses Engineering, School of Chemical Engineering, University of Campinas , Campinas, Brazil.
  • Sousa BKP; Laboratory of Molecular Modeling and Drug Design (LabMol), Faculty of Pharmacy, Universidade Federal de Goiás (UFG) , Goiânia, Brazil.
  • Moreira-Filho JT; Laboratory of Molecular Modeling and Drug Design (LabMol), Faculty of Pharmacy, Universidade Federal de Goiás (UFG) , Goiânia, Brazil.
  • Almeida VM; Laboratory of Molecular Modeling and Drug Design (LabMol), Faculty of Pharmacy, Universidade Federal de Goiás (UFG) , Goiânia, Brazil.
  • Clementino LC; Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética(CBMEG), Universidade Estadual de Campinas (UNICAMP) , Campinas, Brazil.
  • Bourgard C; Laboratory of Tropical Diseases (LDT), Institute of Biology, University of Campinas , Campinas, Brazil.
  • Massirer KB; Laboratory of Tropical Diseases (LDT), Institute of Biology, University of Campinas , Campinas, Brazil.
  • Couñago RM; Department of Chemistry and Molecular Biology, University of Gothenburg , Gothenburg, Sweden.
  • Andrade CH; Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética(CBMEG), Universidade Estadual de Campinas (UNICAMP) , Campinas, Brazil.
  • Sunnerhagen P; Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética(CBMEG), Universidade Estadual de Campinas (UNICAMP) , Campinas, Brazil.
  • Bilsland E; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina, USA.
  • Cassiano GC; Laboratory of Molecular Modeling and Drug Design (LabMol), Faculty of Pharmacy, Universidade Federal de Goiás (UFG) , Goiânia, Brazil.
  • Costa FTM; Center for Research and Advancement of Fragments and Molecular Targets (CRAFT), University of São Paulo , São Paulo, Brazil.
Antimicrob Agents Chemother ; 67(11): e0058923, 2023 11 15.
Article en En | MEDLINE | ID: mdl-37819090
Drug resistance to commercially available antimalarials is a major obstacle in malaria control and elimination, creating the need to find new antiparasitic compounds with novel mechanisms of action. The success of kinase inhibitors for oncological treatments has paved the way for the exploitation of protein kinases as drug targets in various diseases, including malaria. Casein kinases are ubiquitous serine/threonine kinases involved in a wide range of cellular processes such as mitotic checkpoint signaling, DNA damage response, and circadian rhythm. In Plasmodium, it is suggested that these protein kinases are essential for both asexual and sexual blood-stage parasites, reinforcing their potential as targets for multi-stage antimalarials. To identify new putative PfCK2α inhibitors, we utilized an in silico chemogenomic strategy involving virtual screening with docking simulations and quantitative structure-activity relationship predictions. Our investigation resulted in the discovery of a new quinazoline molecule (542), which exhibited potent activity against asexual blood stages and a high selectivity index (>100). Subsequently, we conducted chemical-genetic interaction analysis on yeasts with mutations in casein kinases. Our chemical-genetic interaction results are consistent with the hypothesis that 542 inhibits yeast Cka1, which has a hinge region with high similarity to PfCK2α. This finding is in agreement with our in silico results suggesting that 542 inhibits PfCK2α via hinge region interaction.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Plasmodium / Malaria Falciparum / Malaria / Antimaláricos Tipo de estudio: Diagnostic_studies / Prognostic_studies Idioma: En Revista: Antimicrob Agents Chemother Año: 2023 Tipo del documento: Article País de afiliación: Brasil Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Plasmodium / Malaria Falciparum / Malaria / Antimaláricos Tipo de estudio: Diagnostic_studies / Prognostic_studies Idioma: En Revista: Antimicrob Agents Chemother Año: 2023 Tipo del documento: Article País de afiliación: Brasil Pais de publicación: Estados Unidos