In silico screening and synthesis of reversible and irreversible cruzipain (czp) inhibitors as antichagasic candidates

CERUTTI, JUAN P.; QUEVEDO MA; DEHAEN, W.

Congreso; 56th Advances in organic, bioorganic and pharmaceutical chemistry (LIBLICE-2022); 2022

Chagas disease is a neglected parasitic disease that affects millions of people worldwide and for which no effective treatment is available. In recent years, cruzipain (CZP) has emerged as a promising therapeutic target to meet the need for the development of new antichagasic drugs, due to its vital role in the life cycle of the etiological agent of the disease, the protozoan T. cruzi.In this context, the development of an in silico workflow with high rationality of design is proposed in order to provide a platform capable of describing and recognizing the binding mode of 1,2,3-triazole derivatives against CZP, and to identify the most promising ones to be synthesized and biologically evaluated, in order to propose them as potential new drugs for the treatment of Chagas disease.After in silico synthesis of massive chemical libraries of triazole derivatives by replicating each chemical reaction involved in obtaining the final products and filtering them according to biopharmaceutical and drug-like properties, they were evaluated by a molecular docking procedure that employed the AutoDock4 suite. Each compound was docked against CZP (PDB: …) using native and biased energy grids (Autodock Bias, ). Only those compounds whose docking poses in both systems matched (RMSD lower than …) were considered hits and selected as promising for further synthesis and evaluation, as they were able to generate pharmacophorically appropriate interactions and to adequately position relevant functional groups (e.g. anchors for covalent docking) without being forced by the modified energy maps.In order to test the efficiency of the in silico workflow, XX compounds were synthesized and evaluated against T. cruzi infected cells. Based on the results, xx% of the tested compounds showed efficacy in decreasing total infection by at least 50% at a concentration of 10μM without significantly affecting host cell viability, demonstrating the high predictive capacity of the developed methodology. In conclusion, the presented methodology constitutes a very valuable vHTS platform for the massive screening of large libraries of 1,2,3-triazole derivatives, with high predictive power, being an essential tool for the current synthetic efforts aimed at obtaining new antichagasic drugs.