Kiralj R., Ferreira M. M. C., Pinheiro J. C., Romero O. A. S., “Combined QSAR, Molecular Graphics and Modeling Study on Some C9, C10-substituted Artemisinins with Antimalarial Activity Against Plasmodium Falciparum”. Bournemouth, United Kingdom, 08-13/09/2002: 14th European Symposium on Quantitative Structure-Activity Relationships: Designing Drugs - Problems and Solutions (Euro QSAR 2002), Final Programme Book, Poster No. 045. Session: Section 5 - Modelling the data.

Combined QSAR, Molecular Graphics and Modeling Study on
    Some C9, C10-substituted Artemisinins with Antimalarial
                 Activity Against Plasmodium Falciparum

       Rudolf Kiralj,^a and Márcia M. C. Ferreira,^a José C. Pinheiro,^b Oscar A. S. Romero^{b
       a}Instituto de Química, Universidade Estadual de Campinas, Campinas, 13083-970, SP,
                                                            Brazil
^bDepartamento de Química, Universidade Federal do Pará, Belém, 66075-110, PA, Brazil

At the present time, it is estimated that 40% of the world’s population is exposed to the risk of
contracting malaria, and that every year about 2.7 million people die in consequence of that
disease. The appearance of resistant strains of Plasmodium falciparum to some of drugs in
common clinical usage has made necessary further investigation of new classes of
compounds as artemisinin and its derivatives. The mechanism of artemisinin antimalarial
activity includes heme-catalyzed artemisinin activation into a very reactive radical, which then
could covalently bind to parasite proteins, heme, hemozoin, reduced glutathione or other
parasite molecule.
QSAR study [1] on 17 antimalarial C9, C10-substituted artemisinins against Plasmodium
falciparum (biological activities from literature [2, 3]) was performed by means of quantum
chemical (ab initio HF/6-31G* level), chemometric (Principal Component and Hierarchical
Cluster Analyses, Partial Least Squares Regression) and molecular graphics and modeling
methods. Prediction of antimalarial activities for 10 proposed C9, C10-substituted artemisinins
was performed. Docking of some artemisinins to heme and hemoglobin, as well as structural
studies on heme-receptor complexes, was carried out also. The PLS model with four
latent variables explaining 91.61% of logIC50 variance (Q2 = 0.95 and R2 = 0.96) was
obtained. Molecular descriptors were LUMO+1 energy, atomic charges in C9 and C10, the
maximum number of hydrogen atoms that might make contacts with heme, and a WHIM-3D
index related to molecular symmetry. Two from ten proposed artemisinin derivatives were
predicted with antimalarial activities higher than the compounds reported in literature. The
docking confirmed the PLS results and gave more insight into the nature of heme-artemisinin
and hemoglobin-artemisinin interactions, and made it possible to explain why some
artemisinins can be highly active.
[1] Pinheiro J. C., Ferreira M. M. C., Kiralj R., Reis R. M, Romero O. A. S. Submitted for
publication
[2] Acton N., Karle J. M., Miller R. E. J. Med. Chem. 1993; 36: 2552-7.
[3] Acton N., Klayman D. L. Planta Med. 1987; 53: 266-8.
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