Docking and QM/MM Studies of NS2B-NS3pro Inhibitors: a Molecular Target against the Dengue Virus

Abstract

Dengue virus (DENV) has been characterized as having great clinical importance in the world, as there is no specific treatment against this virus. The NS2B-NS3pro complex is essential for the replication and maturation of DENV and is a potential pharmacological target. The present study aims to evaluate and understand the interactions and affinities (via molecular docking/AutoDock Vina) of 16 peptidomimetic derivatives applied to a NS2B-NS3pro DENV-2 complex constructed by homology modeling (via SWISS-MODEL). Two compounds were selected as potential inhibitors of this protein complex. In addition, these compounds possess important interactions involving Ser135, Gly169 and Tyr161, which have been described previously to be fundamental to the recognition of inhibitors directed to this receptor. Thus, the involvement of these residues is significant pharmacologically because they may contribute to the inhibitory action of this molecular target against DENV.Keywords: dengue, inhibitors, NS2B-NS3pro, molecular modeling IntroductionDengue fever affects approximately 390 million people annually, with higher prevalence in tropical and subtropical regions.1 Dengue virus (DENV) belongs to the genus Flavivirus and Flaviviridae families and is transmitted by the bite from female mosquitoes of the genus Aedes and species A. albopictus and A. aegypti.2 Currently, there is no specific therapy available against DENV; however, palliative treatments to circumvent symptoms caused by the disease are available. DENV has four antigenically distinct serotypes (i.e., DENV1-4), which makes it difficult to develop an effective vaccine. 2-4The viral RNA encodes 10,173 nucleotides that are translated into a polyprotein. This protein is then cleaved by viral and cellular proteases, culminating in the release of three structural proteins (i.e., capsid (C), precursor membrane protein (prM) and envelope (E)) and seven nonstructural proteins (i.e., NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5). 2,5 The serine protease called NS2B-NS3pro DENV has considerable genetic similarity with the analogous West Nile virus (WNV) protease. 6 This protease complex is directly related to replication and maturation of the virus, and it thus represents a promising molecular template for the treatment of these two pathogens. [5][6][7] The N-terminal region of NS2B-NS3pro has 187 amino acids and the catalytic triad His51-Asp75-Ser135 constitutes the active domain of the serine protease, which is essential for cleavage of the viral polyprotein. 6,8 Its catalytic mechanism involves the nucleophilic attack of the oxygen from the serine hydroxyl group and the electrophilic carbon of the peptide bond to be cleaved. 6,[9][10][11] Erbel et al. 6 identified important residues for inhibitor recognition in NS3pro such as Gly151, Gly153 and Tyr161. Regarding the organization of the flaviviral active site, Aleshin et al. 12 demonstrated that a precise spatial arrangement is required to enhance the nucleophilicity of the serine hydroxyl group present in the His-Asp-Ser catalytic t...

Economic and epidemiological impact of dengue illness over 16 years from a public health system perspective in Brazil to inform future health policies including the adoption of a dengue vaccine

“…These include leukopenia (reduction in white blood cells, hemorrhage (bleeding) and circulatory collapse (shock) associated with deaths [22]. Currently, there is no specific antiviral treatment to manage the dengue virus [23][24][25][26]. At the end of 2015, the Brazilian Government approved the first dengue vaccine (CYD-TDV; Dengvaxia ® ) to prevent DENV infection with a reported global efficacy of 60%, recommended for individuals between 9 and 45 years old [27,28].…”

Herb-target virtual screening and network pharmacology for prediction of molecular mechanism of Danggui Beimu Kushen Wan for prostate cancer

“…However, binding affinity values alone may not be fully accurate as an indicator of potential biological activity, since they can have errors of up to 2 kcal/mol 43 . Therefore, an inspection of the number of strong non-covalent interactions between ligands and binding sites should also be used to predict potential bio-activities of herbal compounds, a general approach previously employed in analyses of molecular docking results 44 , 45 . H-bonds are the strongest non-covalent interactions and therefore, the total number of H-bonds formed between ligands and key active site residues can be used to predict the extent to which a ligand may act as an effective inhibitor of PTGS2.…”