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Previous issue date: 2014-07-18 === Dengue (DENVE) ? um importante v?rus pat?geno pertencente ao g?nero Flavivirus. O genoma do v?rus da Dengue, ? constitu?do de RNA envelopado de fita simples e sentido ?nico (+), possui aproximadamente 10.7-11 Kb. O RNA de DENV ? traduzido como uma ?nica poliprote?na. Esta poliprote?na, ? traduzida em 3 prote?nas estruturais (C, prM e E) e 7 n?o estruturais (NS1, NS2A, NS2B, NS3, NS4A, NS4B e NS5). A prote?na NS3 ? uma prote?na multifuncional que al?m de promover o processamento da poliprote?na do genoma viral, tamb?m possui atividade helic?sica, NTP?sica e RTP?sica. A NS3 precisa de cerca de 40 res?duos da prote?na NS2B (que age como cofator) para realizar suas atividades. Os tratamentos de DV atuais s?o principalmente sintom?ticos, n?o existem vacinas eficazes aprovadas e comercializadas, nem drogas antivirais dispon?veis para proteger ou curar a doen?a da dengue. O inibidor tetrapept?dico Bz-Nle-Lys-Arg-Arg-H, (com Ki de 5,8-7,0 ?M) tem sido apresentado na literatura como um potente inibidor da protease NS3 em DV. Sendo uma estrat?gia inteligente para o tratamento da Dengue. O presente trabalho objetivou estudar as intera??es do ligante junto ao s?tio ativo para fornecer uma vis?o mais clara e aprofundada dessas intera??es. Para tal desenvolveu-se um estudo in silico, com utiliza??o de c?lculos de mec?nica qu?ntica, baseada na Teoria do Funcional da Densidade (DFT), com aproxima??es do Gradiente Generalizado (GGA) para descri??o dos efeitos de correla??o e troca. A energia de intera??o de cada amino?cido do s?tio de liga??o, com o ligante foi calculada com base no m?todo de fragmenta??o molecular com capas conjugadas (MFCC). Al?m da energia, foram calculadas as dist?ncias, tipos de intera??es moleculares e grupos at?micos envolvidos. Os modelos te?ricos utilizados foram satisfat?rios e demonstraram uma descri??o mais precisa com a utiliza??o da constante diel?trica ?=20 e 80. Os resultados demonstram que a energia de intera??o do sistema atingiu a converg?ncia em 13,5A. Dentro desse raio de intera??o os res?duos mais importantes foram identificados. Met49, Met84 e Asp81 realizam intera??es de hidrog?nio. Os res?duos Asp79 e Asp75 apresentam elevada energia de atra??o. J? res?duos como Arg54, Arg85 e Lys 131 realizam intera??es de hidrog?nio pr?ximas com o ligante, por?m, aparecem no gr?fico do BIRD possuindo elevada energia de repuls?o com o inibidor. Os resultados tamb?m destacam a import?ncia do res?duo Tyr161 e o envolvimento da tr?ade catal?tica constitu?da por Asp75, Ser135 e His51. === 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 ?
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 ?
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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