Análise in silico de inibidores em potencial de uma proteína de replicação viral (NS5 Rdrp) do vírus da zika.

Abstract

Diseases related to the transmitting vectors of epidemics still concern and are responsible for a high number of mortality and human lethality. The Zika virus (ZIKV) is an arbovirus transmitted by the mosquitoes Aedes aegypti and Aedes albopictus, and recent evidences also points to the mosquito Culex quinquesfasciatus as vector. The first record of this disease was in 1947 in the Zika Forest in Uganda, in Brazil the first ZIKV transmission confirmation arose in mid-April 2015, presented initially in the states of Rio Grande do Norte and Bahia, in the northeast region of the Country. Although symptoms appears to be trivial, Zika fever has become one of the biggest concerns in world public health and Brazil, especially after the recent discovery of its association with cases of microcephaly. Until now, there is no vaccine available for ZIKV, and the treatment is symptomatic. In a recent research was solved the three-dimensional structure of ZIKV NS RdRp X-Ray crystallography, a protein associated with RNA polymerase and important activator of the process of replication of the virus, with this information, came the possibility of making this enzyme a target of new drugs. In this context, theoretical-computational studies are of great value to signal possible inhibitors of this enzyme that work with antiviral, so the current research has as main objective to select in silico possible inhibitors of the protein of NS5 replication. The methodology adopted the following steps: analysis of the three-dimensional structure of the NS5 and its active site; search for by potential inhibitors in the literature and databases of molecules; molecular docking simulations and analysis of interactions in protein-ligands and/or protein-protein complexes generated. Four parameters, considered to be important in the evaluation for the best complex of each docking, were used: The proximity to the active site of the protein (PSAP); the estimated inhibition constant (EIC), the Final Intermolecular Energy (FIE) and the Free Binding Energy (FBE) estimated by the program. The individual energy of the amino acids of NS5 RdRp with the highest interaction with the ligands of interest was quantified by ab initio calculations by Molecular Fraction with Conjugated Caps (MFCC), while using the calculations of the final quantum balance of the interaction protein with the inhibitor candidate linker. The compound INDA obtained the best result, with -1.8eV, followed by TERPENO (1) with -1.41eV, the compound TERPENO (2) and TERPENO (4) indicated respectively -1.00eV and -1.02eV, the two last were the TERPENE (3) with -0.27eV and the QUECERTINE that obtained in its final energy quantum balance of -0.48eV. Thus, it is possible to affirm that all six compounds showed to be negatively expressive, being shown quantically that the ligands have high affinity for the protein, and four of these, with evidence of covalent binding in the active site of NS5 RdRp, stricto sensu, as an irreversible inhibition.The results of this course completion work were highly promising, indicating these six compounds with antiviral potential for inhibition of the NS5 RdRd protein, in view of the various evidences of excellent and comfortable interaction demonstrated by the Molecular Docking and Fractionation Conjugated Caps. Thus, these compounds may aid in the development of a future vaccine that may intervene in the effectiveness of the Zika virus