Integrative Multi-Kinase Approach for the Identification of Potent Antiplasmodial Hits

Author(s):Show less -

Lima, Marilia N. N. ; Cassiano, Gustavo C. ; Tomaz, Kaira C. P. ; Silva, Arthur C. ; Sousa, Bruna K. P. ; Ferreira, Leticia T. ; Tavella, Tatyana A. ; Calit, Juliana ; Bargieri, Daniel Y. ; Neves, Bruno J. ; Costa, Fabio T. M. ; Andrade, Carolina Horta

• Document type: Journal article
• Source: RONTIERS IN CHEMISTR; v. 7, p. 14-pg., 2019-11-21.

Abstract

Malaria is a tropical infectious disease that affects over 219 million people worldwide. Due to the constant emergence of parasitic resistance to the current antimalarial drugs, the discovery of new antimalarial drugs is a global health priority. Multi-target drug discovery is a promising and innovative strategy for drug discovery and it is currently regarded as one of the best strategies to face drug resistance. Aiming to identify new multi-target antimalarial drug candidates, we developed an integrative computational approach to select multi-kinase inhibitors for Plasmodium falciparum calcium-dependent protein kinases 1 and 4 (CDPK1 and CDPK4) and protein kinase 6 (PK6). For this purpose, we developed and validated shape-based and machine learning models to prioritize compounds for experimental evaluation. Then, we applied the best models for virtual screening of a large commercial database of drug-like molecules. Ten computational hits were experimentally evaluated against asexual blood stages of both sensitive and multi-drug resistant P. falciparum strains. Among them, LabMol-171, LabMol-172, and LabMol-181 showed potent antiplasmodial activity at nanomolar concentrations (EC50 <= 700 nM) and selectivity indices >15 folds. In addition, LabMol-171 and LabMol-181 showed good in vitro inhibition of P. berghei ookinete formation and therefore represent promising transmission-blocking scaffolds. Finally, docking studies with protein kinases CDPK1, CDPK4, and PK6 showed structural insights for further hit-to-lead optimization studies. (AU)

• 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: 18/05926-2 - Virtual screening and experimental validation of Plasmodium spp. CK1 (casein kinase 1) inhibitors as potential antimalarial candidates
• Grantee: Kaira Cristina Peralis Tomaz
• Support Opportunities: Scholarships in Brazil - Master
• 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: 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: 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: 12/16525-2 - Plasmodium vivax: pathogenesis and infectivity
• Grantee: Fabio Trindade Maranhão Costa
• Support Opportunities: Research Projects - Thematic 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