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

Author(s):Show less -

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]}

Affiliation

^[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

• Document type: Journal article
• Source: FRONTIERS IN PHARMACOLOGY; v. 9, MAR 6 2018.
• Web of Science Citations: 4

Abstract

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)

• FAPESP's process: 12/16525-2 - Plasmodium vivax: pathogenesis and infectivity
• Grantee: Fabio Trindade Maranhão Costa
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/13119-6 - Cell biology and molecular genetics of hemoparasites
• Grantee: Daniel Youssef Bargieri
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 17/02353-9 - Bioinformatics, Chemiogenomics and Chemioinformatics applied to the Discovery of New Drugs and Biotechnological Products
• Grantee: Fabio Trindade Maranhão Costa
• Support Opportunities: Research Grants - Visiting Researcher Grant - Brazil
• FAPESP's process: 15/20774-6 - Identifying protein kinase inhibitors as antimalarial agents using chemogenomic, bioinfomatics and phenotypic strategies: focus in Plasmodium vivax.
• Grantee: Gustavo Capatti Cassiano
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/16649-4 - Expression, purification and immunological analysis of p. berghei MTRAP
• Grantee: Xiomara Alexandra Gaitán
• Support Opportunities: Scholarships in Brazil - Master