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

Author(s)

Ferreira, Leticia Tiburcio ^[1] ; Borba, Joyce V. B. ^{[1, 2]} ; Moreira-Filho, Jose Teofilo ^[2] ; Rimoldi, Aline ^[1] ; Andrade, Carolina Horta ^[2] ; Costa, Fabio Trindade Maranhao ^[1]

Affiliation

^[1] Univ Estadual Campinas, UNICAMP, Dept Genet Evolut Microbiol & Immunol, Lab Trop Dis Prof Dr Luiz Jacintho da Silva, BR-13083864 Campinas, SP - Brazil

^[2] Univ Fed Goias, Fac Pharm, LabMol, Lab Mol Modeling & Drug Design, BR-74605170 Goiania, Go - Brazil

• Document type: Journal article
• Source: BIOMOLECULES; v. 11, n. 3 MAR 2021.
• Web of Science Citations: 1

Abstract

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. (AU)

• FAPESP's process: 19/21854-4 - Kinase prioritization and discovery of compounds with anti-malarial activity against different stages of Plasmodium vivax using chemogenomics, bioinformatics, cheminformatics, and experimental evaluation tools
• Grantee: Joyce Villa Verde Bastos Borba
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/02171-3 - Investigation of antimalarial activity and molecular targets of natural compounds identified by chemoinformatics against Plasmodium vivax
• Grantee: Letícia Tiburcio Ferreira
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 20/02158-4 - Identifying hypnozonticidal agents using chemogenomic, bioinfomatics and phenotypic strategies: focus in Plasmodium vivax
• Grantee: Aline Rimoldi Ribeiro
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/18611-7 - Development of new tools for search and validation of molecular targets for therapy against Plasmodium vivax
• Grantee: Fabio Trindade Maranhão Costa
• Support Opportunities: Research Projects - Thematic Grants