Browse
Submit Data
Databases
API
Help

Dataset Information

31 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Molecular docking based design of Dengue NS5 methyltransferase inhibitors.

ABSTRACT: Dengue is a viral infection caused by RNA infection of the family Flaviviridae and spread by the Aedes mosquitoes. Dengue NS5 methyltransferase is a known drug target for the disease. Therefore, it is of interest to design potential inhibitors for the target using molecular docking analysis. Our analysis shows the binding of compounds STOCK1N-98943, STOCK1N-98872, STOCK1N-98956, STOCK1N-98865, and STOCK1N-98950 with the protein drug target with optimal binding features for further in vitro and in vivo evaluations.

SUBMITTER: Kausar MA

PROVIDER: S-EPMC6614123 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Molecular docking based design of Dengue NS5 methyltransferase inhibitors.

Kausar Mohd Adnan MA Ali Abrar A Qiblawi Samir S Shahid Sma S Izhari Mohammad Asrar MA Saral Anamika A

Bioinformation 20190530 6

Dengue is a viral infection caused by RNA infection of the family Flaviviridae and spread by the Aedes mosquitoes. Dengue NS5 methyltransferase is a known drug target for the disease. Therefore, it is of interest to design potential inhibitors for the target using molecular docking analysis. Our analysis shows the binding of compounds STOCK1N-98943, STOCK1N-98872, STOCK1N-98956, STOCK1N-98865, and STOCK1N-98950 with the protein drug target with optimal binding features for further in vitro and i ...[more]

PMID: 31312076

Similar Datasets

Screening of commercial cyclic peptide as inhibitor NS5 methyltransferase of Dengue virus through Molecular Docking and Molecular Dynamics Simulation.

Project description:Dengue has become a major global health threat, especially in tropical and subtropical regions. The development of antiviral agent targeting viral replication is really needed at this time. NS5 methyltransferase presents as a novel antiviral target. This enzyme plays an important role in the methylation of 5'-cap mRNA. Inhibition of the NS5 methyltransferase could inhibit dengue virus replication. In this research, two sites of NS5 methyltransferase (S-Adenosyl methionine/SAM binding site and RNA-cap site) were used as targets for inhibition. As much as 300 commercial cyclic peptides were screened to these target sites by means of molecular docking. Analysis of ligand-enzyme binding free energy and pharmacological prediction revealed two best ligands, namely [Tyr123] Prepro Endothelin (110-130), amide, human and Urotensin II, human. According to molecular dynamic simulation, both ligands maintain a stable complex conformation between enzyme and ligand at temperature 310 K and 312 K. Hence, Urotensin II, human is more reactive at 312 K than at 310 K. However, both ligands can be used as potential inhibitor candidates against NS5 methyltransferase of dengue virus with Urotensin II, human exposes more promising activity at 312 K.

| S-EPMC3916815 | biostudies-literature

Looking for inhibitors of the dengue virus NS5 RNA-dependent RNA-polymerase using a molecular docking approach.

Project description:The dengue virus (DENV) nonstructural protein 5 (NS5) contains both an N-terminal methyltransferase domain and a C-terminal RNA-dependent RNA polymerase domain. Polymerase activity is responsible for viral RNA synthesis by a de novo initiation mechanism and represents an attractive target for antiviral therapy. The incidence of DENV has grown rapidly and it is now estimated that half of the human population is at risk of becoming infected with this virus. Despite this, there are no effective drugs to treat DENV infections. The present in silico study aimed at finding new inhibitors of the NS5 RNA-dependent RNA polymerase of the four serotypes of DENV. We used a chemical library comprising 372,792 nonnucleotide compounds (around 325,319 natural compounds) to perform molecular docking experiments against a binding site of the RNA template tunnel of the virus polymerase. Compounds with high negative free energy variation (?G <-10.5 kcal/mol) were selected as putative inhibitors. Additional filters for favorable druggability and good absorption, distribution, metabolism, excretion, and toxicity were applied. Finally, after the screening process was completed, we identified 39 compounds as lead DENV polymerase inhibitor candidates. Potentially, these compounds could act as efficient DENV polymerase inhibitors in vitro and in vivo.

| S-EPMC5066851 | biostudies-literature

Identification of new inhibitors of NS5 from dengue virus using saturation transfer difference (STD-NMR) and molecular docking studies.

Project description:The rapid spread of dengue virus has now emerged as a major health problem worldwide, particularly in tropical and sub-tropical regions. Nearly half of the human population is at risk of getting infection. Among the proteomes of dengue virus, nonstructural protein NS5 is conserved across the genus Flavivirus. NS5 comprises methyltransferase enzyme (MTase) domain, which helps in viral RNA capping, and RNA-dependent RNA polymerase (RdRp) domain, which is important for the virus replication. Negative modulation of NS5 decreases its activity and associated functions. Despite recent advances, there is still an immense need for effective approaches toward drug discovery against dengue virus. Drug repurposing is an approach to identify the new therapeutic indications of already approved drugs, for the treatment of both common and rare diseases, and can potentially lower the cost, and time required for drug discovery and development. In this study, we evaluated 75 compounds (grouped into 15 mixtures), including 13 natural compounds and 62 drugs, by using biophysical methods, for their ability to interact with NS5 protein, which were further validated by molecular docking and simulation studies. Our current study led to the identification of 12 ligands, including both 9 US-FDA approved drugs and 3 natural products that need to be further studied as potential antiviral agents against dengue virus.

| S-EPMC9768849 | biostudies-literature

Molecular Docking Based Screening of Plant Flavonoids as Dengue NS1 Inhibitors.

Project description:Dengue infection has turned into a serious health concern globally due to its high morbidity rate and a high possibility of increase in its mortality rate on the account of unavailability of any proper treatment for severe dengue infection. The situation demands an urgent development of efficient and practicable treatment to deal with Dengue virus (DENV). Flavonoids, a class of phytochemicals present in medicinal plants, possess anti-viral activity and can be strong drug candidates against viruses. NS1 glycoprotein of Dengue virus is involved in its RNA replication and can be a strong target for screening of drugs against this virus. Current study focuses on the identification of flavonoids which can block Asn-130 glycosylation site of Dengue virus NS1 to inhibit viral replication as glycosylation of NS1 is required for its biological functioning. Molecular docking approach was used in this study and the results revealed that flavonoids have strong potential interactions with active site of NS1. Six flavonoids (Deoxycalyxin A; 3,5,7,3',4'-pentahydroxyflavonol-3-O-beta-D-galactopyranoside; (3R)-3',8-Dihydroxyvestitol; Sanggenon O; Epigallocatechin gallate; Chamaejasmin) blocked the Asn-130 glycosylation site of NS1 and could be able to inhibit the viral replication. It can be concluded from this study that these flavonoids could serve as antiviral drugs for dengue infections. Further in-vitro analyses are required to confirm their efficacy and to evaluate their drug potency.

| S-EPMC4135296 | biostudies-literature

New oxindole carboxamides as inhibitors of DENV NS5 RdRp: Design, synthesis, docking and Biochemical characterization.

Project description:Dengue is a mosquito-borne disease caused by the dengue virus belonging to family flaviviridae and has grown to be a major global public health issue. Despite decades of effort, the global comeback of dengue is evidence of the inadequacy of present management techniques. Due to the loss of healthy lives and the depletion of scarce medical resources, dengue has a significant negative economic impact in underdeveloped countries. In recent years, research for tackling the incidences of dengue infection has increased. The structure of the viral genome has been deciphered with the non-structural protein, known as NS5 serving as a potential target. NS5 consisting of an MTase domain involved in RNA capping and an RdRp domain involved in viral replication. In the presented work, a series of new Oxindoline Carboxamide derivatives were designed and synthesized for inhibiting the viral RNA dependent RNA-polymerase (RdRp) activity of DENV. The novel compounds were put through tests including molecular docking and surface plasmon resonance (SPR) binding analysis to evaluate their affinity for the viral protein and their potential as novel inhibitors of the virus. From a total of 12 derivative compounds, four compounds OCA-10c, OCA-10f, OCA-10j & OCA-10i, were found to exhibit high affinity for NS5 RdRp, the KD values being 1.376 μM, 1.63 μM, 7.08 μM & 9.32 μM respectively. Overall, we report novel inhibitors of DENV RdRp activity with potential to be utilized against DENV for treating humans after further optimization.

| S-EPMC10665688 | biostudies-literature

Identification and Characterization of Zika Virus NS5 Methyltransferase Inhibitors.

Project description:The recurring outbreak of Zika virus (ZIKV) worldwide makes an emergent demand for novel, safe and efficacious anti-ZIKV agents. ZIKV non-structural protein 5 (NS5) methyltransferase (MTase), which is essential for viral replication, is regarded as a potential drug target. In our study, a luminescence-based methyltransferase assay was used to establish the ZIKV NS5 MTase inhibitor screening model. Through screening a natural product library, we found theaflavin, a polyphenol derived from tea, could inhibit ZIKV NS5 MTase activity with a 50% inhibitory concentration (IC50) of 10.10 μM. Molecular docking and site-directed mutagenesis analyses identified D146 as the key amino acid in the interaction between ZIKV NS5 MTase and theaflavin. The SPR assay indicated that theaflavin had a stronger binding activity with ZIKV NS5 wild-type (WT)-MTase than it with D146A-MTase. Moreover, theaflavin exhibited a dose dependent inhibitory effect on ZIKV replication with a 50% effective concentration (EC50) of 8.19 μM. All these results indicate that theaflavin is likely to be a promising lead compound against ZIKV.

| S-EPMC8058401 | biostudies-literature

Designing cyclopentapeptide inhibitor as potential antiviral drug for dengue virus ns5 methyltransferase.

Project description:NS5 methyltransferase (Mtase) has a crucial role in the replication of dengue virus. There are two active sites on NS5 Mtase i.e., SAM and RNA-cap binding sites. Inhibition of the NS5 Mtase activity is expected to prevent the propagation of dengue virus. This study was conducted to design cyclic peptide ligands as enzyme inhibitors of dengue virus NS5 Mtase through computational approach. Cyclopentapeptides were designed as ligand of SAM binding site as much as 1635 and 736 cyclopentpeptides were designed as ligand of RNA-cap binding site. Interaction between ligand and NS5 Mtase has been conducted on the Docking simulation. The result shows that cyclopentapeptide CTWYC was the best peptide candidate on SAM binding site, with estimated free binding energy -30.72 kca/mol. Cyclopentapeptide CYEFC was the best peptide on RNA-cap binding site with estimated free binding energy -22.89 kcal/mol. Both peptides did not have tendency toward toxicity properties. So it is expected that both CTWYC and CYEFC ligands could be used as a potential antiviral drug candidates, which can inhibit the SAM and RNA-cap binding sites of dengue virus NS5 Mtase.

| S-EPMC3346019 | biostudies-literature

Docking Studies of Adenosine Analogues with NS5 Methyltransferase of Yellow Fever Virus.

Project description:Yellow fever virus (YFV) is caused by single stranded positive RNA virus called Flavivirus. Till now no specific antiviral agents are available for the treatment of YFV, and despite a commercial YFV vaccine, there are still approximately 30,000 deaths worldwide each year and cases have been increasing in the last 20 years. Here, the effects of adenosine analogues and commercially available adenosine derivative drugs on NS5 methyltransferase of YFV have been performed by the comparative docking study. Based on the docking score, the glide energy and the number of interactions of the adenosine analogues with the Pubchem ID 13792 and 1077 showed the better scoring function than the best ranked commercially available adenosine analogue derived antiviral drug Cc3ado. From the docking result it reveals that these adenosine analogues can bind to the active site of NS5 methyltransferase protein and inhibit the viral replication.

| S-EPMC3298586 | biostudies-literature

Flexibility of NS5 Methyltransferase-Polymerase Linker Region Is Essential for Dengue Virus Replication.

Project description:We examined the function of the conserved Val/Ile residue within the dengue virus NS5 interdomain linker (residues 263 to 272) by site-directed mutagenesis. Gly substitution or Gly/Pro insertion after the conserved residue increased the linker flexibility and created slightly attenuated viruses. In contrast, Pro substitution abolished virus replication by imposing rigidity in the linker and restricting NS5's conformational plasticity. Our biochemical and reverse genetics experiments demonstrate that NS5 utilizes conformational regulation to achieve optimum viral replication.

| S-EPMC4580200 | biostudies-literature

Design, Synthesis and Discovery of N,N'-Carbazoyl-aryl-urea Inhibitors of Zika NS5 Methyltransferase and Virus Replication.

Project description:The recent outbreaks of Zika virus (ZIKV) infection worldwide make the discovery of novel antivirals against flaviviruses a research priority. This work describes the identification of novel inhibitors of ZIKV through a structure-based virtual screening approach using the ZIKV NS5-MTase. A novel series of molecules with a carbazoyl-aryl-urea structure has been discovered and a library of analogues has been synthesized. The new compounds inhibit ZIKV MTase with IC50 between 23-48 μM. In addition, carbazoyl-aryl-ureas also proved to inhibit ZIKV replication activity at micromolar concentration.

| S-EPMC7106487 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data