Estudo dft e in silico de complexos de Bi(iii) com ligantes ditiocarbamatos com propriedades antitumorais.

Abstract

Bismuth complexes with dithiocarbamate have attracted the attention of researchers because of their various applications, such as antimicrobial, antileishmanial and anticancer. These complexes have high cytotoxic activity against cancer cells, and studies show that these complexes have greater activity than the drugs cisplatin, doxorubicin, and tamoxifen. In this study, we investigated the ability of some DFT methods to reproduce the geometry and NMR spectra of Bi(III) complexes with dithiocarbamate ligands, selected on the basis of their proven antitumor activity. We also carried out a DFT study of their electronic properties and an in silico analysis of the pharmacokinetics and interactions of these complexes with the ERBB2 and ERBB3 proteins. The DFT investigation indicated that the M06-L functional with the def2-TZVP basis set provides good results in geometry prediction, while the TPSSh functional with the def2-SVP basis set had good results in 13C NMR chemical shifts. The reactivity descriptors showed that complex 4 is more reactive, with a high possibility of acting as an electrophilic agent. The electrostatic potential maps suggest that bismuth and sulfurs are the main regions of electrophilic reactivity. The in silico results for complex 1 predict its potential as a drug candidate, since it showed pharmacokinetic parameters that suggest good absorption and biodistribution. Complex 2 showed unfavorable hepatotoxicity indices. Complexes 3 and 4 showed potential for causing drug interactions or side effects. Complex 4 also showed that it could cause arrhythmias. The alignment of the receptor sequences, carried out on the Clustal Omega platform, revealed good structural similarity with few mutations in the residues at the site of each kinase. The proteins modeled on the Phyre2 platform showed Ramachandran values above 90%, indicating good quality models, as well as RMSD below 2 Å compared to the experimental models. The blind docking carried out indicates that complexes 1 and 4 can interact with the active site of the receptors. Complex 4 showed better interactions with the site's amino acids, generating lower and more favorable binding energies. These results encourage and serve as a basis for future DFT and in silico studies of Bi(III) dithiocarbamate complexes.