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The Novel Antimalarial Compound Dioncophylline C Forms a Complex with Heme in Solution
Author(s) -
Schwedhelm Kai F.,
Horstmann Martin,
Faber Johan H.,
Reichert Yana,
Bringmann Gerhard,
Faber Cornelius
Publication year - 2007
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200600263
Subject(s) - chemistry , quinoline , heme , paramagnetism , relaxation (psychology) , intermolecular force , stereochemistry , alkaloid , molecule , steric effects , crystallography , organic chemistry , biology , physics , quantum mechanics , neuroscience , enzyme
A structural model of the complex formed between the novel antimalarial compound dioncophylline C (DioC) and its presumed target ferriprotoporphyrin IX heme (FPIX) is presented. The complex structure was calculated with molecular dynamics (MD) simulations using intermolecular distance restraints between DioC and the iron center in FPIX, determined from NMR paramagnetic relaxation. Besides the spin state of the iron and longitudinal relaxation rates of hydrogen nuclei in DioC, the effective correlation time of paramagnetic relaxation was determined from NMR measurements at three different magnetic field strengths. The derived structural model shows high similarity to complexes formed by FPIX and antimalarials of the quinoline family (chloroquine, quinine, quinidine, and amodiaquine). The conformation of DioC is sterically stabilized by a water molecule coordinated to iron in FPIX. This structural feature may provide an important hint at possibilities for a further optimization of novel naphthylisoquinoline alkaloid (NIQ) antimalarial drugs.