Antivirals for allosteric inhibition of Zika virus using a homology model and experimentally determined structure of envelope protein

Abstract

ObjectiveAn approach to inhibiting enveloped flaviviruses is to deter the ability of the envelope protein(s) binding onto glycoproteins. In previous work, using a small ~100-amino acid homology model of Zika virus envelope protein (ZVEP), we proved the susceptibility of Zika virus to inhibition. In this work, we verify the efficacy of the homology model based antiviral search method using a larger protein (>400 amino acids) and comparing the results with the experimentally determined one (PDB ID:5IRE).ResultsBy examining how glycan molecules, small-molecule probes and screened ligands that have a high affinity to ZVEP, we report the mechanics of ZVEP to inhibition via allosteric blockage of the glycan-binding domain while proposing even more possibly potent inhibitors. The small molecular probes based study using the homology model and subsequently verified using actual experimental structure, 5IRE, revealed that ZVEP is druggable. A pharmacophore analysis followed by screening showed at least four ligands that allosterically binds to the glycan binding domain constituted by residues VAL 153 and ASN 154 in 5IRE. Based on further selection criteria ZINC40621658 was identified to have high potential to be a strong antiviral candidate for Zika virus inhibition.

Characterization of a Novel Porphyranase Accommodating Methyl-galactoses at Its Subsites

“…The quality of the constructed model was estimated by QMEAN4 31 and Global Model Quality Estimation (GMQE) scoring functions. 32 The predicted structure was superimposed onto PorA employing the Match Maker function of UCSF Chimera (version 1.13.1). 33 Docking simulation was conducted ■ RESULTS AND DISCUSSION Sequence Analysis.…”

Shaping Polyclonal Responses via Antigen-Mediated Antibody Interference

“…This simple analysis reveals surprising characteristics of the interference structure: First, interactions between epitopes are on average synergistic (m < 0), in contrast to commonly considered mechanisms of Ab interference, such as steric inhibition or glycan reorientation, that are largely competitive. This observation hints at a potential role of allostery in mediating interference; indeed, physical communication between distant parts of HIV Env has been indicated in experimental (Sanders et al, 2013;Julien et al, 2013;Wang et al, 2016) and computational (Sethi et al, 2013) studies and is potentially generic to enveloped viruses (Dowd and Pierson, 2011;Fernando and Fernando, 2017). Furthermore, considerable variation in interaction strength (s$O(1)) indicates that some epitopes engage in strong synergy, whereas others are intensely antagonistic.…”

Molecular dynamics suggests antiviral compounds active against Dengue Virus show similar binding patterns to Zika Virus proteins

“…These structures have few residues in disallowed regions, and were over 90% above the threshold for quality control, so that they could not be considered for downstream evaluations. Homology modeling has become an important tool in virtual screening reports (Agnihotri et al, 2012;Fernando and Fernando, 2017), and particularly useful in finding putative antivirals by molecular docking to homology models (Fernando and Fernando, 2017;Putz et al, 2016). Based on our models, we then sought to investigate possible interactions between the selected compounds and the viral proteins using an all versus all strategy and recording the docking positions as well as their dissociation constants.…”

“…Screening for antivirals against ZIKV has been described as a race (Saiz and Martín-Acebes, 2017). Given the complications associated with the virus, the urgency is important and has produced several antiviral candidates at this point (Fernando and Fernando, 2017;Shiryaev et al, 2017), most of which are compounds repurposed to this end. Based on a literature search, we selected 29 compounds that were commercially available and had been previously shown to be active against Dengue (27) or Zika virus (2) and analyzed ADME/tox properties of this dataset to choose possible combinations to be used.…”

“…Parallel to the developments of in silico drug testing, the computational structural biology groups also developed their methods to generate protein models based on its secondary and tertiary structures for downstream analysis and hypothesis testing. Through the combined information in public databases, ranging from sequencing to crystallographic experimentation, it has become commonplace to generate homology models for a designated target, provided that there is sufficient information in the databases to cover for secondary and tertiary structures coordinates (Agnihotri et al, 2012;Fernando and Fernando, 2017;Shiryaev et al, 2017). In addition, it is of the utmost importance that the genetic information about the viral strains to properly feed the model building process is also present.…”