Ferreira M. M. C., Pereira M. C. S., Kiralj R., "COMPUTATIONAL STUDY OF ARTEMISININ INTERACTION WITH HEME AND ITS POSTERIOR DECOMPOSITION".  Moscow, Russia, 01-05/09/2007: Fourth International Symposium on Computational Methods in Toxicology and Pharmacology Integrating Internet Resources, Book of Abstracts (2007) 95. Poster PO-25.

PO-25
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COMPUTATIONAL STUDY OF  ARTEMISININ INTERACTION WITH HEME  AND
ITS POSTERIOR DECOMPOSITION

Márcia M. C. Ferreira, Mirian C. S. Pereira, Rudolf Kiralj

Instituto de Química, Universidade Estadual de Campinas,  Campinas  13083-862,  SP,  Brazil;
E-mail: marcia@iqm.unicamp.br

Malaria is still one  of  the  diseases  with  serious morbidity  and mortality  statistics worldwide,
especially in countries  in  development.  Another  problem  related to  malaria is appearance of
multidrug   resistance   strains  of  the  Plasmodium species,  especially  of   the   most   mortal
P. falciparum.   A  class  of  novel  substances  based  on  artemisinin  is  a  promising  tool  in
combating malaria.  There  are  sufficient  experimental  and  theoretical evidences  to  consider
that  artemisinin  interacts  with  iron  from  hemoglobin,  forming   free  radicals  that  undergo
various  decomposition  routes  in interactions with parasite molecular architecture,  thus killing
the parasite and disabling its usual defense mechanisms.
The purpose of  the first part  of  this work is to study theoretically stereoelectronic aspects  of
the interactio between  heme  and  artemisinin  in  the  transitional  heme-artemisinin  complex.
The  stability  of  this  complex  is   important  for  the  artemisinin  activation.  Through  semi-
empirical  calculations  using  the  PM3  method,  the  potential  energy  barrier  of  artemisinin
rotation relative to heme in  the  heme-artemisinin  complex was studied  in  vacuum and in the
partially   solvated   state.   The   purpose   of   the  second   part   of   this  work   is  to  study
computationally  artemisinin  decomposition  routes,  which,  after being  activated  by Fe from
heme,  can undergo different decomposition mechanisms  via  free  C-  or  O-centered radicals.
The artemisinin activation is crucial for its biological activity [1].  Ab initio method HF  with 6-
31G** basis  set  was used  in  these calculations,  whilst  heme was simulated by  an  electron.
Electronic  and  Gibbs  energies were  the criteria to identify the most probably  decomposition
pathway.
The minimum heat  of  formation for the complex with  and  without  water molecules is  -702
and -101 kcal mol^-1,  respectively, which corresponds to the dihedral angle C-Fe-O1-O2 of  44º
and 52º around the iron-oxygen O1 bond, respectively. The water molecules bind to heme  via
several hydrogen bonds and  O-H...O and C-H...O interactions,  which  accounts for  -67  kcal
mol^-1.  It  is  observed that th  inclusion  of  water molecules  does  not  affect significantly  the
stability  of   the  heme-artemisinin  complex.  Comparing  O1  and  O2  radical  routes  of  the
artemisinin decomposition scheme,  the  O2 route  is more preferable when C3-O13  and  C12-
C12a bond scissions occur in the seven-membered ring. This route has DG more negative than
all other routes by  11-21  kcal mol^-1,  what is not known in the literature up to  our knowledge.
The authors thank to FAPESP.

[1] Krisnha, S. et al., Drug Resist Updates. 2004, 7, 233 and references cited therein.
 
 

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CMTPI-200795