Computer-aided design of 1,4-naphthoquinone-based inhibitors targeting cruzain and rhodesain cysteine proteases.

摘要: Abstract Chagas disease and Human African Trypanosomiasis (HAT) are caused by Trypanosoma cruzi T. brucei parasites, respectively. Cruzain (CRZ) Rhodesain (RhD) cysteine proteases that share 70% of identity play vital functions in these parasites. These macromolecules represent promising targets for designing new inhibitors. In this context, 26 CRZ 5 RhD 3D-structures were evaluated molecular redocking to identify the most accurate one be utilized as a target. Posteriorly, virtual screening library containing 120 small natural nature-based compounds was performed on both them. total, 14 naphthoquinone-based analogs identified, synthesized, biologically evaluated. five active against RhD, being three them also CRZ. A derivative 1,4-naphthoquinonepyridin-2-ylsulfonamide found molecule, exhibiting IC50 values 6.3 1.8 µM Dynamic simulations at 100 ns demonstrated good stability do not alter targets’ structures. MM-PBSA calculations revealed it presents higher affinity (-25.3 Kcal mol−1) than CRZ, which van der Waals interactions more relevant. mechanistic hypothesis (via C3-Michael-addition reaction) involving covalent mode inhibition compound towards investigated docking DFT B3LYP/6–31 + G* calculations, low activation energy (ΔG‡) providing stable product (ΔG), with 7.78 and − 39.72 mol−1, respectively; similar data literature. Nevertheless, reversibility assay dilution JN-11 is time-dependent reversible inhibitor. Finally, study applies modern computer-aided techniques inhibitors from well-known chemical class products. Then, work could inspire other future studies field, useful potent naphthoquinones