Molecular modeling of the Toxoplasma gondii adenosine kinase inhibitors

Toxoplasma gondii is the most common cause of secondary central nervous system infection in immunocompromised people such as AIDS patients. Since purine 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 benzyladenosines with adenosine kinase.