Análise in silico da interação do fármaco toremifeno com o complexo glicoproteico GP1/GP2 do vírus ebola

Abstract

Ebola virusdisease (EVD) is responsible for outbreaks of infection, markedly by epidemics in West Africa. According to the WHO - World Health Organization, the Ebola of 2014 produced more deaths than all the successes of the previous ebola together. The in vitro virus envelope consists of trimer of a glycoprotein (GP), which is formed by proteins for the formation of GP1 and GP2 subunits. These are related to the anchoring and fusion of the virus in the host cell, respectively. A FL region (Fusion Loop region), contained in the GP2 subunit, also called the fusion loop, behaves as the binding site KZ52 of a potent inhibitor, Toremifene. This ligand acts primarily as an estrogen receptor antagonist during hormone replacement cycles, more recent study demonstrated strong and effective binding with an Ebola virus glycoprotein. In fact, tests of classical performance indicators were triggered by GPD and the activation of GP2 was triggered prematurely, which prevents the fusion between the virus and the host endosome.In this dissertation, Molecular Modeling techniques, especially the Molecular Fractionation Method with Conjugated Coats (MFCC), were used to calculate the binding energies between the amino acid residues of the GP glycoprotein of the Ebola virus and the drug Toremifeno, to characterize energetically the affinity to the formation of this biocomplex. The structural and energetic understanding of the toremifene-GP1 / GP2 complex will reveal the inhibitory mechanism of this ligand and, subsequently, will guide the development of previously non-existent anti-Ebola drugs. As results, residues ASP522 (-10.39 Kcal / mol), GLU100 (-8.59 Kcal / mol), TYR517 (-6.50 Kcal / mol), THR519 (-3.24 Kcal / mol ), LEU186 (-2.77 Kcal / mol) and LEU515 (-2.76 Kcal / mol) are mainly responsible for the stability of the Ebola virus Toremifene / GP1-GP2 complex; The order of interactional relevance of drug regions is i (e4: -63.02 kcal / mol; e40: -26.39)> iii (e4: -23.66 kcal / mol; e40: -21, 11 Kcal / mol)> ii (e4: -10.36 kcal / mol; e40: - 10.13 Kcal / mol); [iii] in terms of the energy contribution of the secondary structures of the GP1 / GP2 receptor, the β-11 (GP1) leaf and the β-18 (GP2) leaf are the ones that have the most permissible amino acids at the binder coupling, β-10 (GP1) and the α-18 (GP2) helix have the residues that cause the binder to repulse to the coupling pocket.