Virtual screening and experimental validation of Plasmodium spp. CK1 (casein kinase 1) inhibitors as potential antimalarial candidates

• Grant number: 18/05926-2
• Support Opportunities: Scholarships in Brazil - Master
• Start date: June 01, 2018
• End date: September 30, 2020
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Fabio Trindade Maranhão Costa
• Grantee: Kaira Cristina Peralis Tomaz
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated scholarship(s): 19/17062-5 - Plasmodium spp. kinase inhibitors as potential antimalarial candidates: virtual screening and experimental validation on yeast target-based system, BE.EP.MS

Abstract

Malaria is one of the major public health concerns in most tropical regions around the globe. Parasitic resistance to current antimalarials brings the need for new compounds to control the disease. Protein casein kinase 1 (CK1) is conserved among Plasmodium species, highly expressed throughout the parasite's blood cycle and shows physical interaction with the Rab-5B protein, which makes part of metabolic control. Moreover, reverse genetics studies have shown that this protein is essential for the development of the blood stage of the parasite. With this information, we suggest that CK1 may be a promising molecular target against Plasmodium spp. The present project aims to identify PvCK1 inhibitors that are active against malaria parasite. A virtual screening will be performed to select molecules that bind with less energy to the 3D model constructed of the protein PvCK1 (i, ii). Subsequently, the compounds that obtain good results will be experimentally validated in vitro against both asexual (iii) and sexual (iv) blood stages of P. falciparum and their cytotoxicity will be assessed using mammalian cells (COS-7 and HepG2) (v). Ex vivo assays against asexual P. vivax blood stages will be performed with the most promising compounds (vi). Finally, the target of the compounds as well as their specificity against the parasite protein will be validated by yeast screening assays genetically engineered by colleagues in our group to express CK1 of P. vivax and human (vii). Thus, we hope to help in the search for active compounds that can be developed in new antimalarials. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

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.; et al. Integrative Multi-Kinase Approach for the Identification of Potent Antiplasmodial Hits. FRONTIERS IN CHEMISTRY, v. 7, NOV 21 2019. (18/05926-2, 13/13119-6, 18/07007-4, 17/02353-9, 17/18611-7, 12/16525-2, 18/24878-9, 15/20774-6)

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.; et al. Integrative Multi-Kinase Approach for the Identification of Potent Antiplasmodial Hits. RONTIERS IN CHEMISTR, v. 7, p. 14-pg., 2019-11-21. (17/02353-9, 18/05926-2, 13/13119-6, 18/24878-9, 18/07007-4, 15/20774-6, 12/16525-2, 17/18611-7)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

TOMAZ, Kaira Cristina Peralis. Virtual screening and experimental validation of casein kinases (CKs) inhibitors from Plasmodium spp. with antimalarial potential. 2021. Master's Dissertation - Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia Campinas, SP.