Anti-malarial drug development using models of enzyme structure

Zhe Li, Xiaowu Chen, Eugene Davidson, Oren Zwang, Chandana Mendis, Christine S. Ring, William R. Roush, Glenn Fegley, Rongshi Li, Philip J. Rosenthal, Garson K. Lee, George L. Kenyon, Irwin D. Kuntz, Fred E. Cohen

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


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 languageEnglish (US)
Pages (from-to)31-37
Number of pages7
JournalChemistry and Biology
Issue number1
StatePublished - Sep 1994
Externally publishedYes


  • 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


Dive into the research topics of 'Anti-malarial drug development using models of enzyme structure'. Together they form a unique fingerprint.

Cite this