Bioquímica quântica da capreomicina e da estreptomicina em complexo com o ribossomo bacteriano
Tuberculosis is a disease caused by Mycobacterium tuberculosis, and according to the World Health Organization, only in 2015 occurred 10.4 million new cases reported and 1.4 million deaths. The number of cases of patients infected with antimicrobial resistant strains most used is increasing, requiri...
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| Formato: | Dissertação |
| Idioma: | por |
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| Endereço do item: | https://repositorio.ufrn.br/jspui/handle/123456789/22614 |
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| Resumo: | Tuberculosis is a disease caused by Mycobacterium tuberculosis, and according to the World Health Organization, only in 2015 occurred 10.4 million new cases reported and 1.4 million deaths. The number of cases of patients infected with antimicrobial resistant strains most used is increasing, requiring the use of second-line drugs. Capreomycin and streptomycin are part of the group, and are antibiotics whose mechanism of action is the inhibition of protein synthesis. However, its binding mechanisms in their sites are distinct: capreomycin is able to bind to both ribosomal (30S and 50S) subunits, whereas streptomycin binds to the smaller ribosomal subunit (30S), and interacts with some points of S12 protein. Through crystallographic data and computational simulations, we calculated the interaction energy of capreomycin and streptomycin with each of the residues component of their sites using the Density Functional Theory (DFT) and Molecular Fractionation with Conjugated Caps (MFCC). The results showed energy values of each nucleotide belonging to binding site of these two drugs, as well as the amino acids of the S12 protein with which streptomycin interacts. Thus, for capreomycin in the 30S subunit, residues present in a radius of up to 14 Å distant from the drug, totaling 44 residues; and in the 50S subunit, 30 nucleotides were analyzed, and were distributed up to the 30Å radius distance. Regarding streptomycin, 60 nucleotides distributed up to 12.5 Å away from the drug in the 30S subunit, and 25 amino acids of the S12 protein with up to 15 Å were taken into account. We also identify the contributions of hydrogen bonds and hydrophobic interactions in drug-receptor interactions; the regions of the drugs that most contributed to the anchorages of these in their binding sites; as well as the identification of residues that are most associated with mutations and consequent resistance. |
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