Artificial Intelligence Applied to the Rapid Identification of New Antimalarial Candidates with Dual-Stage Activity

Author(s):Show less -

Lima, Marilia N. N. ^[1] ; Borba, Joyce V. B. ^{[1, 2]} ; Cassiano, Gustavo C. ^{[3, 2]} ; Mottin, Melina ^[1] ; Mendonca, Sabrina S. ^[1] ; Silva, Arthur C. ^[1] ; Tomaz, Kaira C. P. ^[2] ; Calit, Juliana ^[4] ; Bargieri, Daniel Y. ^[4] ; Costa, Fabio T. M. ^[2] ; Andrade, Carolina H. ^{[1, 2]}

Affiliation

^[1] Univ Fed Goias, Fac Pharm, LabMol Lab Mol Modeling & Drug Design, Rua 240, Qd 87, BR-74605170 Goiania, Go - Brazil

^[2] Inst Biol, Dept Genet Evolut Microbiol & Immunol, Lab Trop Dis Prof Dr Luiz Jacintho da Silva, BR-13083970 Campinas, SP - Brazil

^[3] Univ Nova Lisboa, Inst Higiene & Med Trop, Global Hlth & Trop Med GHTM, Lisbon - Portugal

^[4] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, BR-05508000 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: CHEMMEDCHEM; v. 16, n. 7, p. 1093-1103, APR 8 2021.
• Web of Science Citations: 0

Abstract

Increasing reports of multidrug-resistant malaria parasites urge the discovery of new effective drugs with different chemical scaffolds. Protein kinases play a key role in many cellular processes such as signal transduction and cell division, making them interesting targets in many diseases. Protein kinase 7 (PK7) is an orphan kinase from the Plasmodium genus, essential for the sporogonic cycle of these parasites. Here, we applied a robust and integrative artificial intelligence-assisted virtual-screening (VS) approach using shape-based and machine learning models to identify new potential PK7 inhibitors with in vitro antiplasmodial activity. Eight virtual hits were experimentally evaluated, and compound LabMol-167 inhibited ookinete conversion of Plasmodium berghei and blood stages of Plasmodium falciparum at nanomolar concentrations with low cytotoxicity in mammalian cells. As PK7 does not have an essential role in the Plasmodium blood stage and our virtual screening strategy aimed for both PK7 and blood-stage inhibition, we conducted an in silico target fishing approach and propose that this compound might also inhibit P. falciparum PK5, acting as a possible dual-target inhibitor. Finally, docking studies of LabMol-167 with P. falciparum PK7 and PK5 proteins highlighted key interactions for further hit-to lead optimization. (AU)

• 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: 13/13119-6 - Cell biology and molecular genetics of hemoparasites
• Grantee: Daniel Youssef Bargieri
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 17/18611-7 - 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
• FAPESP's process: 18/24878-9 - Search for Plasmodium transmission-blocking compounds using new experimental models
• Grantee: Juliana Calit Paim
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 18/07007-4 - Identification of new antimalarial treatments through a target-centred "drug repositioning" approach
• Grantee: Elizabeth Bilsland
• Support Opportunities: Regular Research Grants
• 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