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Published on: October 5, 2019
The novel antimalarial compound dioncophylline C forms a complex with heme in solution
Kai F Schwedhelm1, Martin Horstmann, Johan H Faber
1Department of Experimental Physics 5, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Chemmedchem
|February 23, 2007
Summary
Researchers modeled the dioncophylline C (DioC) and heme (FPIX) complex, revealing structural similarities to existing antimalarials. This finding offers insights for optimizing novel naphthylisoquinoline alkaloid (NIQ) drugs.
Area of Science:
- Medicinal Chemistry
- Structural Biology
- Parasitology
Background:
- Antimalarial drug resistance necessitates the development of novel therapeutic agents.
- Ferriprotoporphyrin IX heme (FPIX) is a validated target for antimalarial drugs.
- Dioncophylline C (DioC) is a novel antimalarial compound belonging to the naphthylisoquinoline alkaloid (NIQ) class.
Purpose of the Study:
- To elucidate the structural complex formed between dioncophylline C (DioC) and ferriprotoporphyrin IX heme (FPIX).
- To compare the structural model of the DioC-FPIX complex with those of known quinoline-based antimalarials.
- To identify structural features that could guide the optimization of novel NIQ antimalarial drugs.
Main Methods:
- Molecular dynamics (MD) simulations were employed to calculate the complex structure.
- Intermolecular distance restraints were derived from NMR paramagnetic relaxation measurements.
- NMR measurements at three magnetic field strengths were used to determine spin states, relaxation rates, and correlation times.
Main Results:
- A structural model of the DioC-FPIX complex was successfully generated.
- The DioC-FPIX complex structure exhibits significant similarity to complexes formed by FPIX with quinoline antimalarials.
- A water molecule coordinated to the iron in FPIX was found to sterically stabilize the conformation of DioC.
Conclusions:
- The structural model provides a molecular basis for understanding DioC's antimalarial mechanism.
- The stabilization by a coordinated water molecule offers a potential avenue for drug optimization.
- This study highlights the potential of NIQ compounds as a promising class of antimalarial drugs.
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