A series of dipeptides containing sulfur groups were modeled to understand their inhibitor activity against leishmaniasis. The trypanthione molecule, which acts as a reducing agent in several vital processes, is responsible for maintaining the parasite’s cellular thiol redox balance. The antimonic (SbV) acid (Sb2O5.nH2O) is being evaluated as a drug to stop leishmaniasis. In this study, two model clusters were investigated: A [(Sb2O10H8)]-2 coordinated to cysteine in continuum water medium, and B [Sb7O28H21] coordinated to trypanothione with a glucose adduct. We report here DFT (TPSS/def2-TZVP) results on the binding energy of cysteine and trypanthione complexed to these clusters. Analysis was made of the electronic structure, Mulliken charges, Gibbs free energy and HOMO-LUMO energy levels as well as the dipole moment. Focus was on theoretical thermochemistry data for receptor-substrate interactions to identify ligand-cluster inhibition to help unravel the mechanism of inhibition. In addition, the acidity of Sb2O5.nH2O, surface-passivation, the electrostatic forces between charged cluster surface and dipeptide inhibitors present relevant effects through proton transfer or hydrogen mobility. Further cluster stability comparisons show a lower Gibbs free energy of binding in A/cysteine (20 Kcal/mol) vs. (30 Kcal/mol) in B/ trypanthione. Given their tight coordination through H-transfer, B/trypanthione is predicted to be the most potent of the inhibitors modeled.

DFT modelling of the stability and the electronic structure of (Sb2O5,nH2O) cluster towards cysteine, glucose and trypanothione complexation

ACS Fall 2020 Virtual Meeting

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