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OPTIMIZATION OF SmTGR INHIBITORS USING A FRAGMENT-BASED DRUG DESIGN (FBDD) APPROACH

OPTIMIZATION OF SmTGR INHIBITORS USING A FRAGMENT-BASED DRUG DESIGN (FBDD) APPROACH

Rocío Riveros Maidana, Lauro Ribeiro de Souza Neto, Nicholas Furnham, Raymond J. Owens, José Brandão Neto, Frank von Delft, Ana Carolina Ramos Guimarães and Floriano Paes Silva Junior

Schistosomiasis is a neglected tropical disease caused by Schistosoma spp. Praziquantel (PZQ) is the unique drug used for the treatment of the disease. Despite the success of the treatment, the concern about the emergence of strains less sensitive to PZQ, and the possibility of evolution of drug resistance are growing. Thioredoxin glutathione reductase of Schistosoma mansoni (SmTGR) is a validated drug target that plays a crucial role in the redox homeostasis of the parasite inside the human host. The Fragment-based Drug Design (FBDD) strategy consists of screening low molecular weight compounds against macromolecular targets (usually proteins) of clinical relevance. These small molecular fragments can bind at one or more sites on the target and act as starting points for the development of lead compounds. An FBDD screening campaign was performed obtaining 32 fragments that bind to 8 sites located at the SmTGR surface. From those sites, one secondary site was selected and fragments that bind to that site were optimized using a fragment-growing approach. The optimization was performed using the program AutoGrow 3.0. A total of 42 new ligands were generated from the initial fragments.