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

Frontiers in Pharmacology

Eugene N. Muratov¹  Juliana Calit²  Daniel Y. Bargieri²  Pedro V. L. Cravo³  Marilia N. N. Lima⁴  Rodolpho C. Braga⁴  Cleber C. Melo-Filho⁴  Vinicius M. Alves⁴  Bruno J. Neves⁶  Fabio T. M. Costa⁷  Gustavo C. Cassiano⁷  Carolina H. Andrade⁷ 

[1] Department of Chemical Technology, Odessa National Polytechnic University, Odessa, Ukraine;Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil;Global Health and Tropical Medicine Centre, Unidade de Parasitologia Médica, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisbon, Portugal;LabMol – Laboratory for Molecular Modeling and Drug Design, Faculty of Pharmacy, Federal University of Goiás, Goiânia, Brazil;Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States;Laboratory of Cheminformatics, PPG-SOMA, University Center of Anápolis/UniEVANGELICA, Anápolis, Brazil;Laboratory of Tropical Diseases – Prof. Dr. Luiz Jacintho da Silva, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, UNICAMP, Campinas, Brazil;

关键词: malaria;    virtual screening;    QSAR;    Plasmodium falciparum;    dUTPase;    transmission blocker;   

DOI  :  10.3389/fphar.2018.00146

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown