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

Autor(es)

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: BIOMOLECULES; v. 11, n. 3 MAR 2021.
• Citações Web of Science: 1

Resumo

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)

• Processo FAPESP: 19/21854-4 - Priorização de quinases e descoberta de compostos com atividade antimalárica contra diferentes estágios de Plasmodium vivax utilizando ferramentas de quimiogenômica, bioinformática, quimioinformática e ensaios experimentais
• Beneficiário: Joyce Villa Verde Bastos Borba
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 19/02171-3 - Investigação da atividade antimalárica e de alvos moleculares de compostos naturais identificados por quimioinformática contra Plasmodium vivax
• Beneficiário: Letícia Tiburcio Ferreira
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 20/02158-4 - Identificação de moléculas com ação hipnozonticida baseada em análises de quimiogenômica, bioinformática e fenotípicas: enfoque em Plasmodium vivax
• Beneficiário: Aline Rimoldi Ribeiro
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 17/18611-7 - Desenvolvimento de novas ferramentas para busca e validação de alvos moleculares para terapia contra Plasmodium vivax
• Beneficiário: Fabio Trindade Maranhão Costa
• Modalidade de apoio: Auxílio à Pesquisa - Temático