De novo design approaches targeting an envelope protein pocket to identify small molecules against dengue virus (original) (raw)
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Receptor-Guided De Novo Design of Dengue Envelope Protein Inhibitors
Inhibitor design associated with the dynamics of dengue envelope protein at pre-fusion stage is a prominent strategy to interfere fusion transition of dengue virus with the host cell membrane. Receptor-guided de novo inhibitors were designed based on the knowledge of co-crystallized detergent, β-octyl glucoside. Pharmacophore features distribution showed the preference of aromatic groups with H bonding features connected to aliphatic bulky group as the skeleton for inhibitor design. Molecular dynamic simulations revealed (2R)-2-[(6-amino-1-oxohexan-2-yl)amino]-4-[6-(4-phenylpiperidine-1-yl)-1,2- benzoxazol-3-yl]butanoate as the probable binder which developed extensive conservative interactions despite the local pocket residues movements especially from kl β-hairpin, the key structural unit for initiating conformational changes required for fusion transition. The electronic and hydrophobic potentials also indicated that butanoate molecule as the initial lead for envelope protein inhibitors.
Epitopes based drug design for dengue virus envelope protein: A computational approach
Computational biology and chemistry, 2017
Dengue virus (DENV) has emerged as a rapidly spreading epidemic throughout the tropical and subtropical regions around the globe. No suitable drug has been designed yet to fight against DENV, therefore, the need for safe and effective antiviral drug has become imperative. The envelope protein of DENV is responsible for mediating the fusion process between viral and host membranes. This work reports an in silico approach to target B and T cell epitopes for dengue envelope protein inhibition. A conserved region "QHGTI" in B and T cell epitopes of dengue envelope glycoprotein was confirmed to be valid for targeting by visualizing its interactions with the host cell membrane TIM-1 protein which acts as a receptor for serotype 2 and 3. A reverse pharmacophore mapping approach was used to generate a seven featured pharmacophore model on the basis of predicted epitope. This pharmacophore model as a 3D query was used to virtually screen a chemical compounds dataset "Chembridg...
In silico drug designing studies on dengue virus envelope protein
World Journal of Pharmaceutical sciences, 2018
The key proteins involved in causing dengue are seven major proteins, which are considered as major therapeutic targets for dengue drug development. Recent studies have reported positive for dengue virus envelope protein in dysregulation of causing dengue process in humans. Dragon fruit seed phytochemicals are reported to have antioxidant and antiviral properties. In the present study we studied the binding efficiency of 11 compounds that are present in the dragon fruit seeds with dengue virus envelope protein through Insilico method. By our virtual screening and docking result, we found that the Compound A and Compound C have highest binding affinity with the dengue virus envelope protein and also we predicted the binding site amino acid residues and the nature of hydrogen bonding. However more invivo experimental validation of our results with animal models will enlighten the development of more potent drugs from these compounds for treatment of dengue. Sushmitha and Sathyamurthy, World J PharmSci 2018; 6(9): 138-143
Discovery of Immunologically Inspired Small Molecules That Target the Viral Envelope Protein
ACS Infectious Diseases, 2018
Dengue virus is a major human pathogen that infects up to 350 million people annually leading to approximately 500,000 hospitalizations due to severe dengue. Since the only marketed vaccine, Dengvaxia, has recently been shown to increase disease severity in those lacking natural immunity, antivirals to prevent or treat DENV infection represent a large, unmet medical need. Small molecules that target the dengue virus envelope protein, E, on the surface of the virion could act analogously to antibodies by engaging E extracellularly to block infection. Progress towards direct-acting antivirals against E has been hindered by the protein's lack of a conserved, "druggable" site and a shortage of robust, target-based assays suitable for screening and medicinal chemistry studies. Here we demonstrate that the dengue envelope (E) protein offers a tractable drug target for preventing dengue infection by developing a target-based assay using a recombinantly expressed dengue serotype 2 E protein. We performed a high-throughput screen of ~20,000 compounds followed by secondary assays to confirm target-binding and antiviral activity and counter-screens to exclude compounds with nonspecific activities. These efforts yielded eight distinct chemical leads that inhibit dengue infection by binding to E and preventing E-mediated membrane fusion with potencies equal to or greater than previously described small molecule inhibitors of E. We show that a subset of these compounds inhibit viruses representative of the other three dengue serotypes and Zika virus. This work provides tools for discovery and *
Structure-Based Design of Antivirals against Envelope Glycoprotein of Dengue Virus
Viruses, 2020
Dengue virus (DENV) presents a significant threat to global public health with more than 500,000 hospitalizations and 25,000 deaths annually. Currently, there is no clinically approved antiviral drug to treat DENV infection. The envelope (E) glycoprotein of DENV is a promising target for drug discovery as the E protein is important for viral attachment and fusion. Understanding the structure and function of DENV E protein has led to the exploration of structure-based drug discovery of antiviral compounds and peptides against DENV infections. This review summarizes the structural information of the DENV E protein with regards to DENV attachment and fusion. The information enables the development of antiviral agents through structure-based approaches. In addition, this review compares the potency of antivirals targeting the E protein with the antivirals targeting DENV multifunctional enzymes, repurposed drugs and clinically approved antiviral drugs. None of the current DENV antiviral ...
Structural Optimization and De Novo Design of Dengue Virus Entry Inhibitory Peptides
PLoS Neglected Tropical Diseases, 2010
Viral fusogenic envelope proteins are important targets for the development of inhibitors of viral entry. We report an approach for the computational design of peptide inhibitors of the dengue 2 virus (DENV-2) envelope (E) protein using high-resolution structural data from a pre-entry dimeric form of the protein. By using predictive strategies together with computational optimization of binding ''pseudoenergies'', we were able to design multiple peptide sequences that showed low micromolar viral entry inhibitory activity. The two most active peptides, DN57opt and 1OAN1, were designed to displace regions in the domain II hinge, and the first domain I/domain II beta sheet connection, respectively, and show fifty percent inhibitory concentrations of 8 and 7 mM respectively in a focus forming unit assay. The antiviral peptides were shown to interfere with virus:cell binding, interact directly with the E proteins and also cause changes to the viral surface using biolayer interferometry and cryo-electron microscopy, respectively. These peptides may be useful for characterization of intermediate states in the membrane fusion process, investigation of DENV receptor molecules, and as lead compounds for drug discovery.
Antiviral Research, 2013
Please cite this article in press as: Yang, C.-C., et al. Characterization of an efficient dengue virus replicon for development of assays of discovery of small molecules against dengue virus. Antiviral Res. (2013), http://dx.84 end (5 0 CS) and the 3 0 UTR (3 0 CS) of all mosquito-borne flavivirus 85 genomes (Alvarez et al., 2005a, b; Hahn et al., 1987; Khromykh 86 et al., 2001; Polacek et al., 2009; Villordo and Gamarnik, 2009). 87 Additionally, it has been reported that a hairpin element, cHP, 88 which is located in the N-terminus of the capsid-coding region, di-89 rects start codon selection and recruits factors associated with the 90 replicase machinery during viral RNA replication (Clyde et al., 91 2008; Clyde and Harris, 2006). Recently, another motif, the 5 0 92 downstream AUG region (5 0 DAR), which is located downstream 93 of the AUG region of core gene and is complementary to the 3 0 94 end of dengue genome, was demonstrated to be essential for 95 RNA replication and involved in genome circularization of DENV 96 and WNV (Fayzulin et al., 2006; Friebe and Harris, 2010; Friebe 97 et al., 2011; Groat-Carmona et al., 2012). These results indicated 98 that cis-acting elements within the flavivirus capsid gene play cru-99
Dengue Virus and its Structure - A Promising Target for Drug Discovery
International Journal of Pharmaceutical and Life Sciences
Dengue is the most endemic disease of last decade; this disease is caused by the infection of Dengue Virus (DENV). This virus completes its lifecycle in Aides mosquito and human. There are several vaccines against this virus but they only prevent from disease and reduce the risk of death. DENV have three serotypes all with minor difference in structure. Immunity against one serotype does not impart immunity against all serotypes in case of infection, it may cause disease extremity. Many researchers believe that it is difficult to develop a vaccine against all serotypes because of difference in structure. A potent inhibitor is required for the disease to be treated. In this study we considered its (DENV) structure and mode of infection so that we can develop or search a promising target and compound for treatment of this disease.
Identification of novel target sites and an inhibitor of the dengue virus E protein
Journal of Computer-Aided Molecular Design, 2009
Dengue and related flaviviruses represent a significant global health threat. The envelope glycoprotein E mediates virus attachment to a host cell and the subsequent fusion of viral and host cell membranes. The fusion process is driven by conformational changes in the E protein and is an essential step in the virus life cycle. In this study, we analyzed the pre-fusion and post-fusion structures of the dengue virus E protein to identify potential novel sites that could bind small molecules, which could interfere with the conformational transitions that mediate the fusion process. We used an in silico virtual screening approach combining three different docking algorithms (DOCK, GOLD and FlexX) to identify compounds that are likely to bind to these sites. Seven structurally diverse molecules were selected to test experimentally for inhibition of dengue virus propagation. The best compound showed an IC 50 in the micromolar range against dengue virus type 2. Keywords Dengue virus Á Envelope protein Á Flavivirus Á Virtual drug screening Abbreviations BSA Bovine serum albumin DENV Dengue virus DMEM Dulbecco's modified Eagle's medium FCS Fetal calf serum JEV Japanese encephalitis virus MTT Methyl thiazole tetrazolium PDB Protein Data Bank PBS Phosphate buffered saline pfu Plaque-forming units TBEV Tick-borne encephalitis virus WNV West Nile virus Electronic supplementary material The online version of this article (
Antiviral research, 2009
The flaviviruses comprise a large group of related viruses, many of which pose a significant global human health threat, most notably the dengue viruses (DENV), West Nile virus (WNV) and yellow fever virus (YFV). Flaviviruses enter host cells via fusion of the viral and cellular membranes, a process mediated by the major viral envelope protein E as it undergoes a low pH induced conformational change in the endosomal compartment of the host cell. This essential entry stage in the flavivirus life cycle provides an attractive target for the development of antiviral agents. We performed an in silico docking screen of the Maybridge chemical database within a previously described ligand binding pocket in the dengue E protein structure that is thought to play a key role in the conformational transitions that lead to membrane fusion. The biological activity of selected compounds identified from this screen revealed low micromolar antiviral potency against dengue virus for two of the compounds. Our results also provide the first evidence that compounds selected to bind to this ligand binding site on the flavivirus E protein abrogate fusion activity. Interestingly, one of these compounds also has antiviral activity against both WNV (kunjin strain) and YFV.