QSAR-Based Virtual Screening of Natural Products Database for Identification of Potent Antimalarial Hits

Biomolecules

卷:11

CarolinaHorta Andrade¹  JoséTeófilo Moreira-Filho¹  JoyceV. B. Borba²  LetíciaTiburcio Ferreira²  Aline Rimoldi²  FabioTrindade Maranhão Costa² 

[1] Laboratory of Molecular Modeling and Drug Design, LabMol, Faculty of Pharmacy, Federal University of Goiás, Goiânia, GO 74605-170, Brazil;

[2] Laboratory of Tropical Diseases Prof. Dr. Luiz Jacintho da Silva, Department of Genetics, Evolution, Microbiology and Immunology, University of Campinas-UNICAMP, Campinas, SP 13083-864, Brazil;

关键词: Plasmodium falciparum;    natural products;    virtual screening;    experimental validation;    QSAR;    ADME;   

DOI  :  10.3390/biom11030459

来源: DOAJ

【 摘 要 】

With about 400,000 annual deaths worldwide, malaria remains a public health burden in tropical and subtropical areas, especially in low-income countries. Selection of drug-resistant Plasmodium strains has driven the need to explore novel antimalarial compounds with diverse modes of action. In this context, biodiversity has been widely exploited as a resourceful channel of biologically active compounds, as exemplified by antimalarial drugs such as quinine and artemisinin, derived from natural products. Thus, combining a natural product library and quantitative structure–activity relationship (QSAR)-based virtual screening, we have prioritized genuine and derivative natural compounds with potential antimalarial activity prior to in vitro testing. Experimental validation against cultured chloroquine-sensitive and multi-drug-resistant P. falciparum strains confirmed the potent and selective activity of two sesquiterpene lactones (LDT-597 and LDT-598) identified in silico. Quantitative structure–property relationship (QSPR) models predicted absorption, distribution, metabolism, and excretion (ADME) and physiologically based pharmacokinetic (PBPK) parameters for the most promising compound, showing that it presents good physiologically based pharmacokinetic properties both in rats and humans. Altogether, the in vitro parasite growth inhibition results obtained from in silico screened compounds encourage the use of virtual screening campaigns for identification of promising natural compound-based antimalarial molecules.

【 授权许可】

Unknown