QSAR-Driven Design and Discovery of Novel Compounds With Antiplasmodial and Transmission Blocking Activities

Autor(es):Mostrar menos -

Lima, Marilia N. N. ^[1] ; Melo-Filho, Cleber C. ^[1] ; Cassiano, Gustavo C. ^[2] ; Neves, Bruno J. ^{[1, 3]} ; Alves, Vinicius M. ^[1] ; Braga, Rodolpho C. ^[1] ; Cravo, Pedro V. L. ^[4] ; Muratov, Eugene N. ^{[5, 6]} ; Calit, Juliana ^[7] ; Bargieri, Daniel Y. ^[7] ; Costa, Fabio T. M. ^[2] ; Andrade, Carolina H. ^{[2, 1]}

Afiliação do(s) autor(es)

^[1] Univ Fed Goias, Fac Pharm, Lab Mol Modeling & Drug Design, LabMol, Goiania, Go - Brazil

^[2] Univ Estadual Campinas, Inst Biol, Dept Genet Evolut Microbiol & Immunol, Lab Trop Dis Prof Dr Luiz Jacintho da Silva, Campinas, SP - Brazil

^[3] Univ Ctr Anapolis UniEVANGELICA, SOMA, PPG, Lab Cheminformat, Anapolis - Brazil

^[4] Univ Nova Lisboa, Inst Higiene & Med Trop, Unidade Parasitol Med, Global Hlth & Trop Med Ctr, Lisbon - Portugal

^[5] Univ N Carolina, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Lab Mol Modeling, Chapel Hill, NC - USA

^[6] Odessa Natl Polytech Univ, Dept Chem Technol, Odessa - Ukraine

^[7] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN PHARMACOLOGY; v. 9, MAR 6 2018.
• Citações Web of Science: 4

Resumo

Malaria is a life-threatening infectious disease caused by parasites of the genus Plasmodium, affecting more than 200 million people worldwide every year and leading to about a half million deaths. Malaria parasites of humans have evolved resistance to all current antimalarial drugs, urging for the discovery of new effective compounds. Given that the inhibition of deoxyuridine triphosphatase of Plasmodium falciparum (PfdUTPase) induces wrong insertions in plasmodial DNA and consequently leading the parasite to death, this enzyme is considered an attractive antimalarial drug target. Using a combi-QSAR (quantitative structure-activity relationship) approach followed by virtual screening and in vitro experimental evaluation, we report herein the discovery of novel chemical scaffolds with in vitro potency against asexual blood stages of both P. falciparum multidrug-resistant and sensitive strains and against sporogonic development of P. berghei. We developed 2D- and 3D-QSAR models using a series of nucleosides reported in the literature as PfdUTPase inhibitors. The best models were combined in a consensus approach and used for virtual screening of the ChemBridge database, leading to the identification of five new virtual PfdUTPase inhibitors. Further in vitro testing on P. falciparum multidrug-resistant (W2) and sensitive (3D7) parasites showed that compounds LabMol-144 and LabMol-146 demonstrated fair activity against both strains and presented good selectivity versus mammalian cells. In addition, LabMol-144 showed good in vitro inhibition of P. berghei ookinete formation, demonstrating that hit-to-lead optimization based on this compound may also lead to new antimalarials with transmission blocking activity. (AU)

• Processo FAPESP: 12/16525-2 - Plasmodium vivax: patogênese e infectividade
• Beneficiário: Fabio Trindade Maranhão Costa
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/13119-6 - Biologia celular e genética molecular de hemoparasitas
• Beneficiário: Daniel Youssef Bargieri
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 17/02353-9 - Bioinformática, Quimiogenômica e Quimioinformática aplicados à Descoberta de Novos Fármacos e Produtos Biotecnológicos
• Beneficiário: Fabio Trindade Maranhão Costa
• Modalidade de apoio: Auxílio à Pesquisa - Pesquisador Visitante - Brasil
• Processo FAPESP: 15/20774-6 - Identificação de inibidores de quinases com atividade antimalárica baseado em análises de quimiogenômica, bioinformática e fenotípicas: enfoque em Plasmodium vivax.
• Beneficiário: Gustavo Capatti Cassiano
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 16/16649-4 - Expressão, purificação e análise imunológica da proteína MTRAP de p. berghei
• Beneficiário: Xiomara Alexandra Gaitán
• Modalidade de apoio: Bolsas no Brasil - Mestrado