Abstract
Background: The trophozoite stage of the malaria parasite infects red blood cells. During this phase of their lifecycle, the parasites use hemoglobin as their principal source of amino acids, using a cysteine protease to degrade it. We have previously reported a three-dimensional model of this cysteine protease, based on the structures of homologous proteases, and the use of the program DOCK to identify a ligand for the malaria protease. Results: Here we describe the design of improved ligands starting from this lead. Ligand design was based on the predicted configuration of the lead compound docked to the model three-dimensional structure of the protease. The lead compound has an IC50 of 6 μM, and our design/synthesis strategy has resulted in increasingly potent derivatives that block the ability of the parasites to infect and/or mature in red blood cells. The two best derivatives to date have IC50s of 450 nM and 150 nM. Conclusions: A new class of anti-malarial chemotherapeutics has resulted from a computational search that was based on a model of the target protease. Despite the lack of a detailed experimental structure of the target enzyme or the enzyme-inhibitor complex, we have been able to identify compounds with increased potency. These compounds approach the activity of chloroquine (IC50 = 20 nM), but have a distinct mechanism of action. This series of compounds could thus lead to new therapies for chloroquine-resistant malaria.
Original language | English (US) |
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Pages (from-to) | 31-37 |
Number of pages | 7 |
Journal | Chemistry and Biology |
Volume | 1 |
Issue number | 1 |
DOIs | |
State | Published - Sep 1994 |
Externally published | Yes |
Keywords
- docking strategies
- homology modeling
- novel anti-malarial compounds
- structure-activity relationships
- trophozoite cysteine protease
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmacology
- Drug Discovery
- Clinical Biochemistry