chapter 1 - Bentham Science

162 Chemoinformatics: Directions Toward Combating Neglected Diseases, 2012, 162-173
Teodorico C. Ramalho, Matheus P. Freitas and Elaine F. F. da Cunha (Eds)
All rights reserved - © 2012 Bentham Science Publishers
CHAPTER 8
Molecular Modeling of the Toxoplasma gondii Adenosine Kinase
Inhibitors
Daiana Teixeira Mancini * , Elaine F. F. da Cunha, Teodorico C. Ramalho and
Matheus P. Freitas
Department of Chemistry, Federal University of Lavras, P.O. Box 3037, 37200-000, Lavras, MG, Brazil
Abstract: Toxoplasma gondii (T. gondii) is the most common cause of secondary central nervous
system infection in immunocompromised persons such as AIDS patients. Since purine salvage is
essential for T. gondii and for other parasitic protozoa, inhibition of this salvage should block parasite
growth. T. gondii adenosine kinase (EC 2.7.1.20) is the major route of adenosine (purine nucleoside)
metabolism in this parasite. Four-Dimensional Quantitative Structure-Activity Relationship (4D-QSAR)
analysis was applied to a series of 41 inhibitors of T. gondii adenosine kinase. Optimized 4D-QSAR
models were constructed by Genetic Algorithm (GA) optimization and partial least squares (PLS)
fitting, and evaluated by the leave-one-out cross-validation method. Moreover, we have used docking
approaches to study the binding orientations and predict binding affinities of some benzyladenosines
with adenosine kinase.
Keywords: Toxoplasma gondii, adenosine kinase, docking
1. INTRODUCTION
The parasitic protozoon Toxoplasma gondii (T. gondii) is the etiologicagent of toxoplasmosis, a parasitic
disease widespread amongvarious warm-blooded animals, including humans [1]. Toxoplasmosis is known to be
one of themost prevalent parasitic infections of the central nervous system and causes lethal encephalitisin
immunocompromised patients such those with acquired immunodefficiency syndrome (AIDS) [2]. In spite of
the tragicconsequences of toxoplasmosis, the therapy of the disease hasnot changed in the last 20 years [1]. The
current treatment consists of combinations of drugs, such as Pyrimethamine (Daraprim ® ), trimethoprimsulfamethoxazole
(Bactrin ® ), Sulfadiazine (Triglobe ® ) or Clindamycin (Dalacin ® ) [4]. Newborns with
congenital toxoplasmosis are treated for at least a year with a combination of antibiotics. If the woman develops
toxoplasmosis during pregnancy, her doctor may prescribe medications that reduce the risk of children
developing congenital toxoplasmosis. These drugs include spiramycin (Rovamicina ® Periodontil ® ),
Pyrimethamine and Sulfadiazine. To decrease the possibility of developing congenital problems (at birth)
related to the drugs, the type and duration of treatment will depend on which quarter she is pregnant [3].
T. gondii is apurine auxotroph incapable of de novo purine biosynthesis and depends on salvage pathways
for its purine requirements [4]. However, T. gondii can efficiently salvage purine nucleosides and
nucleobases for macromolecular synthesis. The most efficiently utilized precursor is reported to be
adenosine monophosphate (AMP) and adenosine kinase (AK, EC2.7.1.20) is the major enzyme in the
salvage of purines in these parasites [5]. T. gondii adenosine kinase (TgAK) is a 363-residue (39.3 kDa)
monomeric protein, that catalyzes the phosphorylation of adenosine to adenosine 5´-monophosphate
(AMP), using the g-phosphate group of ATP as the phosphate donor [2]. Since purine salvage is essential
for T. gondii and for other parasitic protozoa, inhibition of this salvage should block parasite growth.
Benzyladenosine analogues are known in the literature as subversive substrates, i.e., they are preferentially
metabolized to the nucleotide level and become selectively toxicfor the parasite, but not for human adenosine
kinase [6-8]. Kouni et al. described a series of benzyl adenosine analogues that act as potent and
*Address correspondence to Daiana Teixeira Mancini; Department of Chemistry, Federal University of Lavras, P.O. Box 3037,
37200-000, Lavras, MG, Brazil. E-mail: elaine_cunha@dqi.ufla.br