Estudo in silico das interações da protease NS3-NS2B de DENV-2 com o inibidor peptídico Bz-nKRR-H com finalidades terapêuticas
Dengue virus is an important patogen that causes Dengue desease in all world, and belongs to Flavivirus gender. The virus consists of enveloped RNA with a single strand positive sense, 11Kb genome. The RNA is translated into a polyprotein precursor, wich is cleaved into 3 structural proteins (C,...
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| Formato: | Dissertação |
| Idioma: | por |
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Universidade Federal do Rio Grande do Norte
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| Endereço do item: | https://repositorio.ufrn.br/jspui/handle/123456789/19509 |
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| Resumo: | Dengue virus is an important patogen that causes Dengue desease in all world, and belongs
to Flavivirus gender. The virus consists of enveloped RNA with a single strand positive sense, 11Kb
genome. The RNA is translated into a polyprotein precursor, wich is cleaved into 3 structural
proteins (C, prM e E) and 7 non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B e NS5).
The NS3 is a multifunctional protein, that besides to promote the polyprotein precursor cleavage,
also have NTPase, helicase and RTPase activity. The NS3 needs a hydrophilic segment of 40
residues from the transmembrane NS2B protein (who acts like cofator) to realize this functions.
Actually, there's no vacines available on the market, and the treatment are just symptomatic. The
tetrapeptide inhibitor Bz-Nle-Lys-Arg-Arg-H (Ki de 5,8-7,0 M) was showed as a potent inhibitor μ
for NS3prot in Dengue virus. That is a inteligent alternative to treat the dengue desease. The present
work aimed analyse the interactions of the ligand bounded to the activity site to provid a clear and
depth vision of that interaction. For this purpouse, it was conducted an in silico study, by using
quantum mechanical calculations based on Density Functional Theory (DFT), with Generalized
Gradient approximation (GGA) to describe the effects of exchange and correlation. The interaction
energy of each amino acid belonging to the binding site to the ligand was calculated the using the
method of molecular fragmentation with conjugated caps (MFCC). Besides energy, we calculated
the distances, types of molecular interactions and atomic groups involved. The theoretical models
used were satisfactory and show a more accurate description when the dielectric constant = 20 ε
and 80 was used. The results demonstrate that the interaction energy of the system reached
convergence at 13.5 A. Within a radius of 13,5A the most important residues were identified.
Met49, Met84 and Asp81 perform interactions of hydrogen with the ligant. The Asp79 and Asp75
residues present high energy of attraction. Arg54, Arg85 and Lys 131 perform hydrogen interactions
with the ligand, however, appear in BIRD graph having high repulsion energy with the inhibitor.
The data also emphasizes the importance of residue Tyr161 and the involvement of the catalytic
triad composed by Asp75, His51 and Ser135 |
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