Last Updated: 15/10/2025
Studies of structural biology and medicinal chemistry for the discovery of enolase enzyme inhibitors from Plasmodium falciparum
Objectives
This research project aims to develop new antimalarial compounds targeting the enolase enzyme from Plasmodium falciparum, which is crucial for the parasite’s energy metabolism. By optimizing lead compounds identified from the “Malaria Box” collection, the project will utilize advanced structural biology and medicinal chemistry techniques to enhance their efficacy and safety profiles.
Malaria is a global public health problem with high mortality rates. In Brazil, malaria has a tremendous impact, where around 500,000 new cases per year are reported. In this scenario, new therapeutic alternatives with an innovative mechanism of action are extremely necessary. Glycolytic enzymes play important roles in Plasmodium biology. For example, in the intra-erythrocyte stages of P. falciparum the tricarboxylic acid cycle is absent, therefore the parasite uses only the glycolytic pathway for energy. The enolase enzyme (EC 4.2.1.11) catalyzes the reversible interconversion of 2-phosphoglycerate to phosphoenolpivurate and it was found that the enzyme is associated with the nucleus, digestive vacuole, cytoskeleton, anchored in membranes, plasma and involved in the process of cell invasion, displaying moonlighting functions. Therefore, Pf-ene is an attractive and validated target for the development of antimalarial drugs. The lead compounds were identified in the screening of the “Malaria Box” collection against the P. falciparum enolase enzyme (Pfeno). The screening identified 50 compounds as promising Pfeno inhibitors. IC50 values determined for the most potent compounds are in the low micromolar range. Among the main active compounds, the quinoline (MMV000570) and benzimidazole (MMV666607) derivatives are attractive for property optimization studies. Modern methods and strategies in structural molecular biology and medicinal chemistry will be used to design compounds with optimized properties through the integration of organic synthesis, SAR studies and structure-based design. The compounds will be evaluated in a standardized biological assay against the target enzyme and, to guide the planning of new derivatives, crystallographic structures of ligand-protein complexes will be obtained. The Institute of Physics of São Carlos – USP has world-renowned experience in structural biology and medicinal chemistry that was reinforced by the creation of the Center for Research and Innovation in Biodiversity and Pharmaceuticals (CIBFar-CEPID), providing modern facilities for the characterization of proteins and interactions with binders. The CIBFar-CEPID laboratories have complete infrastructure to carry out all the steps proposed in this research project.
Jul 2016 — Feb 2018
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