ORIGINAL RESEARCH Molecular modeling of the Toxoplasma gondii adenosine kinase inhibitors Elaine F. F. da Cunha • Daiana Teixeira Mancini • Teodorico C. Ramalho Received: 16 March 2010 / Accepted: 5 January 2011 / Published online: 29 January 2011 Ó Springer Science+Business Media, LLC 2011 Abstract Toxoplasma gondii is the most common cause of secondary central nervous system infection in immu- nocompromised people such as AIDS patients. Since pur- ine salvage is essential for T. gondii and other parasitic protozoa, inhibition of its salvage pathway, by blocking adenosine kinase (EC 2.7.1.20), the main responsible for the metabolism of adenosine (purine nucleoside) can block the parasite growth. Having this in mind, 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 the interaction energies of some benzyladeno- sines with adenosine kinase. Keywords Toxoplasma gondii  Adenosine kinase  Molecular modeling Introduction The parasitic protozoon Toxoplasma gondii is the etiologic agent of toxoplasmosis, a parasitic disease widespread among several warm-blooded animals, including humans (El Kouni et al., 1999). Toxoplasmosis is known to be one of the most prevalent parasitic infections of the central nervous system and causes lethal encephalitis in immuno- compromised patients such those with acquired immuno- deficiency syndrome (AIDS) (Al Safarjalania et al., 2007). In spite of the tragic consequences of toxoplasmosis, the therapy for this disease has not changed in the last 20 years (El Kouni et al., 1999). The current treatment consists on combinations of drugs, such as Pyrimethamine (Dara- prim Ò ), trimethoprim-sulfamethoxazole (Bactrin Ò ), Sulfa- diazine (Triglobe Ò ), or Clindamycin (Dalacin Ò ) (Ngo et al., 2000). Newborns with congenital toxoplasmosis are treated for at least a year with a combination of antibiotics. If a woman develops toxoplasmosis during pregnancy, her doctor may prescribe medications to reduce the risk of the child contract congenital toxoplasmosis. These drugs include spiramycin (Rovamicina Ò Periodontil Ò ), Pyri- methamine, 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 is the pregnancy (Petersen, 2007). Toxoplasma gondii is a purine auxotroph incapable of de novo purine biosynthesis and depends on salvage pathways for its purine requirements (Ngo et al., 2000). The most efficiently utilized precursor reported is adenosine mono- phosphate (AMP) and adenosine kinase (AK, EC 2.7.1.20) is the major enzyme in the salvage of purines in these parasites (Reddy et al., 2007). T. gondii adenosine kinase (TgAK) is a 363-residue (39.3 kDa) monomeric protein, that catalyzes the phosphorylation of adenosine to adeno- sine 5 0 -monophosphate (AMP), using the g-phosphate group of ATP as the phosphate donor (Al Safarjalania et al., 2007). 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 E. F. F. da Cunha (&)  D. T. Mancini  T. C. Ramalho Department of Chemistry, Federal University of Lavras, Lavras, Minas Gerais 37200-000, Brazil e-mail: elaine_cunha@dqi.ufla.br 123 Med Chem Res (2012) 21:590–600 DOI 10.1007/s00044-011-9554-z MEDICINAL CHEMISTR Y RESEARCH