Current data from the World Health Organization show that about 13 million people are infected with Trypanosoma cruzi, the causative protozoan agent of Chagas´ Disease. It also indicates an annual incidence of 200.000 cases in 15 countries. This disease remains a priority health problem considering not only the number of afflicted patients, but also taking into account other associated factors including unsatisfactory chemotherapy, which is by its turn accounted for low effectiveness in the chronic phase of the disease, lack of efficacy due to naturally resistant T. cruzi strains, and serious side effects of drugs nowadays in use. The most noticeable symptoms observed in chronic patients are irreversible damage to the heart and digestive tract, causing 14.000 deaths per year and considerable morbidity. In addition, the socioeconomic and medical costs of care represent a huge impact in economy from the standpoint of both the society and the family of the patient.
One of the potential drug targets for the development of new chemotherapeutic agents against Chagas´ Disease is the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from Trypanosoma cruzi. Our aim consists of searching for new chemicals that could be able to selectively block the activity of this enzyme. For this purpose, a Virtual High Throughput Screening (vHTS) using a receptor-based method has been applied.
A large chemical database was submitted to an early filtering approach in order to select structures with relevant characteristics that better agree with expected features present in drug like compounds. Then, the selected molecules were evaluated using the computational programs GOLD® and FLEXX® based on different scoring functions. Afterwards, a combination of scoring functions (consensus scoring) yielded the set of 50 best ranked molecules.
The chemical diversity combined within the selected compounds reveals interactions of great importance for a better comprehension of the molecular recognition process involved. Also, the variety of chemical structures recognized by vHTS strongly contributed to identification of newly potential chemical classes which could essentially possess improved selectivity and potency against T. cruzi GAPDH.
Supported by: FAPESP, CNPq