In silico screening and synthesis of reversible and irreversible Cruzipain inhibitors as antichagasic candidates

CERUTTI, JUAN PABLO; QUEVEDO, MARIO ALFREDO; DEHAEN, WIM

Liblice

Congreso; 56th Advances in Organic, Bioorganic and Pharmaceutical Chemistry; 2022

Division of Organic, Bioorganic and Pharmaceutical Chemistry of the Czech Chemical Society

Chagas disease is a neglected parasitic disease that affects millions of people world-wide and for which no effective treatment is available. In recent years, cruzipain (CZP) hasemerged as a promising therapeutic target to meet the need of the development of newantichagasic drugs, due to its crucial role in the life cycle of T. cruzi, the etiological agentof Chagas. The search of potent and selective inhibitors of CZP constitutes a very activeresearch topic, and considering that the catalytic site of CZP has been fully characterized,computer-aided structure based design represents a powerful tool towards inhibitor design.In this work, we present an in silico workflow designed for the virtual high through-put screening of libraries of potential 1,4-disubstituted 1,2,3-triazole inhibitors. The workflowinitiates with the construction of chemical libraries by combinatorial enumeration of diversesynthetic pathways based on readily available commercial reactants. The resulting chemicallibraries (containing typically hundreds of thousands of compounds) were afterwards subjec-ted to massive molecular docking using GPU infrastructure as implemented in AutoDock4-GPU and AutoDock4 Bias. Docking results were filtered through real-time fingerprint inter-action analyses to detect hit compounds. A serie of 18 compounds were identified as themost promising candidates, including both potential reversible and irreversible inhibitors. Onthe basis of these results, the corresponding protocols were applied and optimized towardstheir synthesis, confirming the purification of the products which were further subjected totheir biological evaluation by using T.cruzi infected cell models. The biological activity resultsdemonstrated that 5 (27 %) out of the 18 evaluated compounds exhibited promising results,bearing an inhibition above 50 % of T.cruzi viability. In a second optimization round, the mostpotent compound was used as lead structure to further apply the vHTS workflow to optimizeintermolecular interactions focused in the R1 region. The most promising compounds werefurther synthesised and submitted to biological evaluation (results to be determined).In conclusion, the presented methodology constitutes a valuable vHTS platform for themassive screening of large libraries of 1,2,3-triazole derivatives as antichagasic compounds,exhibiting a significant predictive power.