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New Approaches to Structure-Based Discovery of Dengue Protease Inhibitors

S. Tomlinson, R. Malmstrom, S. Watowich
2009 Infectious Diseases - Drug Targets  
This review discusses current and newly implemented structure-based computational efforts to discover antivirals that target the DENV NS3 protease, although it is clear that these computational tools can  ...  Dengue virus (DENV), a member of the family Flaviviridae, presents a tremendous threat to global health since an estimated 2.5 billion people worldwide are at risk for epidemic transmission.  ...  Comparison of the dengue NS3 protease [63] and the dengue NS2B-NS3 protease [68] . Ribbon diagram representation of (A) NS3 and (B) NS2B-NS3 proteins.  ... 
doi:10.2174/1871526510909030327 pmid:19519486 fatcat:z3g7wb3fonhcdddlw56axh2jfu

Designing cyclic peptide inhibitor of dengue virus NS3-NS2B protease by using molecular docking approach

Usman Sumo Friend Tambunan, Samira Alamudi
2010 Bioinformation  
Seven cyclopentapeptide inhibitors were designed in this study against dengue virus type 2 (DEN-2) NS3-NS2B protease: CKRRC, CGRRC, CRGRC, CRTRC, CTRRC, CKRKC and CRRKC.  ...  Thus, the cyclopentapeptide is proposed as a potential inhibitor to the NS3-NS2B protease activities of DEN-2.  ...  Acknowledgement: We are grateful to Ridla Bakri PhD, Chairman of Department of Chemistry, Faculty of Mathematics and Natural Science, University of Indonesia for his support of this research.  ... 
doi:10.6026/97320630005250 pmid:21364826 pmcid:PMC3055701 fatcat:acfpya66qje2zd7ekalyye7yh4

Molecular Dynamics of the Dengue Virus NS3/NS2B Protease in Presence of Inhibitor or Substrate

Maria Carolina P. Lima, Gustavo de Miranda Seabra
2014 Biophysical Journal  
The computationally less expensive empirical ligand and structure based methods require training a predictive model to yield accurate free energy estimates.  ...  In addition, these studies can provide fundamental insights into how ligand binding regulates protein function.  ... 
doi:10.1016/j.bpj.2013.11.1534 fatcat:sgm4xg6bcra6xalkjle32meoyu

Insights to Substrate Binding and Processing by West Nile Virus NS3 Protease through Combined Modeling, Protease Mutagenesis, and Kinetic Studies

Keith J. Chappell, Martin J. Stoermer, David P. Fairlie, Paul R. Young
2006 Journal of Biological Chemistry  
Using a combination of molecular fitting of substrates to the active site of the crystal structure of NS3, site-directed enzyme and cofactor mutagenesis, and kinetic studies on proteolytic processing of  ...  A key enzyme that is essential for viral replication is the viral protease NS2B-NS3, which is highly conserved among all flaviviruses.  ...  Recently reported crystal structures for NS2B/NS3 proteases of both WNV and Den2 (6) provide new structural insights to flaviviral proteases in ligand-bound conformations.  ... 
doi:10.1074/jbc.m607641200 pmid:17052977 fatcat:mhjzkbo67rhtrolmjxnfdapl4y

Interactomics of Blebbistatin

Miklós Képiró, Boglárka H. Várkuti, György Hegyi, Mihály Kovács, András Málnási-Csizmadia
2013 Biophysical Journal  
hand, a nutrient-how the receptor senses these agonists in healthy and diseased states.  ...  extracellular domain (ECD) of CaSR with various spectroscopic methods including the tryptophan fluorescence titration, circular dichroism (CD) and nuclear magnetic resonance (NMR) as well as molecular  ...  Drugs for the Discovery of Inhibitors of Dengue Virus NS2B-NS3 Protease by Docking, Consensus Scoring, and Molecular Dynamics Simulations Aldo Segura-Cabrera, Carlos A.  ... 
doi:10.1016/j.bpj.2012.11.2252 fatcat:ln3pjsxi2fcsfcp4ta5cam4g6a

In Silico Prediction of the Phosphorylation of NS3 as an Essential Mechanism for Dengue Virus Replication and the Antiviral Activity of Quercetin

Lamya Alomair, Fahad Almsned, Aman Ullah, Mohsin S. Jafri
2021 Biology  
Dengue virus infection is a global health problem for which there have been challenges to obtaining a cure.  ...  We employed computational methods based on structure-function relationships between human host kinases and viral nonstructural protein 3 (NS3) to understand viral replication inhibitors' therapeutic effect  ...  Appendix A Figure 1 . 1 NS3 crystal structure. (A) The crystal structure of the NS3 Protease-Helicase from Dengue virus (PDB: 2VBC). The Protease domain (N-terminal, residues 20-168) is shown in red.  ... 
doi:10.3390/biology10101067 pmid:34681164 fatcat:i4wpxf3lpng4pghcgy2k244d4y

Mechanisms of Proteolytic Enzymes and Their Inhibition in QM/MM Studies

Brigitta Elsässer, Peter Goettig
2021 International Journal of Molecular Sciences  
In line with this, computational chemistry based on experimental structures came up with studies on all major protease classes in recent years; examples of aspartic, metallo-, cysteine, serine, and threonine  ...  In this overview, a few examples demonstrate the high potential of the QM/MM approach for sophisticated pharmaceutical compound design and supporting functions in the analysis of biomolecular structures  ...  Similarly, the reaction mechanism of the HCIV-related NS3 protease of the Dengue virus with its cofactor NS2B exhibited a stepwise nucleophilic attack and protonation at the scissile bond during the acylation  ... 
doi:10.3390/ijms22063232 pmid:33810118 pmcid:PMC8004986 fatcat:4gc4ck72uvg7xonbaveqtss5bq

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

Daniel F. de Lima Neto, Anderson P Soares, Shahab Z Pour, Aida S Ortiz, Caio M Freire, Patrick Neuhaus, Carlos FS Bonafe
2018 bioRxiv   pre-print
Here we have applied these methods on compounds that were previously shown to be active against Dengue virus in vitro, taking the structural information of such compounds and applying docking methods to  ...  A molecular dynamics approach was also used to refine the docking results.  ...  of the helicase activity of the NS3 protein, thus providing further insights into the action mechanisms of each compound against Dengue virus, as originally suggested by the respective authors of each  ... 
doi:10.1101/309351 fatcat:j35dvkyndnhpdbo4qmxxsukxgq

Genetic and structural analyses of ssRNA viruses pave the way for the discovery of novel antiviral pharmacological targets

Dimitrios Vlachakis
2021 Molecular Omics  
In the era of big data and artificial intelligence a lot of new discoveries have influenced the field of antiviral drug design and pharmacophore identification. Viruses have always been a...  ...  disruption of the NS2B-NS3 interaction emerges as a possible alternative approach in the design of anti-flaviviral drugs.  ...  Flavivirus protease is a complex between the NS3 protein and a hydrophobic core within the viral NS2B protein, which acts as an essential cofactor.  ... 
doi:10.1039/d0mo00173b pmid:33725065 fatcat:edvbbsxm4zf5pect65nzb5rtnq

Molecular docking and QSAR theoretical model for prediction of phthalazinone derivatives as new class of potent dengue virus inhibitors

Samuel Ndaghiya Adawara, Gideon Adamu Shallangwa, Paul Andrew Mamza, Abdulkadir Ibrahim
2020 Beni-Suef University Journal of Basic and Applied Sciences  
The improvement of existing agents that can inhibit the dengue virus is therefore of utmost importance.  ...  Also, in this study, molecular docking simulation was carried between dengue virus serotype 2 protease (PDB CODE: 6mol) and some selected phthalazinone derivatives (compounds 1, 2, 7, 11, and 21).  ...  Figures 2a, b, 6a-d, and 7a ,b showed prepared structure of the target (NS2B-NS3) and 3D structure of the prepared ligand 21, 2D interaction type for ligand 1, 2, 7, and 11 with different amino acids in  ... 
doi:10.1186/s43088-020-00073-9 fatcat:6oicuqdoojcqbmg6zrpdsdgbju

Discovery of novel West Nile Virus protease inhibitor based on isobenzonafuranone and triazolic derivatives of eugenol and indan-1,3-dione scaffolds

André S. de Oliveira, Poliana A. R. Gazolla, Ana Flávia C. da S. Oliveira, Wagner L. Pereira, Lívia C. de S. Viol, Angélica F. da S. Maia, Edjon G. Santos, Ítalo E. P. da Silva, Tiago A. de Oliveira Mendes, Adalberto M. da Silva, Roberto S. Dias, Cynthia C. da Silva (+4 others)
2019 PLoS ONE  
The West Nile Virus (WNV) NS2B-NS3 protease is an attractive target for the development of therapeutics against this arboviral pathogen.  ...  Molecular docking calculations predicted a recognition pattern involving the residues His51 and Ser135, which are members of the catalytic triad of the WNV NS2B-NS3 protease.  ...  Viral protease performs the cleavage of some sites: NS2A-NS2B, NS2B-NS3, NS3-NS4A and NS4B-NS5.  ... 
doi:10.1371/journal.pone.0223017 pmid:31557229 pmcid:PMC6762200 fatcat:4bqa2u4l2rg3fa2duux4nqsq6e

Peptide-Based Subunit Vaccine Design of T- and B-Cells Multi-Epitopes against Zika Virus Using Immunoinformatics Approaches

Vivitri Dewi Prasasty, Karel Grazzolie, Rosmalena Rosmalena, Fatmawaty Yazid, Fransiskus Xaverius Ivan, Ernawati Sinaga
2019 Microorganisms  
In this study, a collection of Zika proteomes was used to find the best candidates for T- and B-cell epitopes using the immunoinformatics approach.  ...  The Zika virus disease, also known as Zika fever is an arboviral disease that became epidemic in the Pacific Islands and had spread to 18 territories of the Americas in 2016.  ...  The structure for NS2B was obtained from a complexed structure with the protease domain of dengue NS3 [113] .  ... 
doi:10.3390/microorganisms7080226 pmid:31370224 pmcid:PMC6722788 fatcat:s7jcassopfhylgj426zduliini

Facile Synthesis and In Vitro Activity of N-Substituted 1,2-Benzisothiazol-3(2H)-ones against Dengue Virus NS2BNS3 Protease

Farwa Batool, Muhammad Saeed, Hafiza Nosheen Saleem, Luisa Kirschner, Jochen Bodem
2021 Pathogens  
Several new N-substituted 1,2-benzisothiazol-3(2H)-ones (BITs) were synthesised through a facile synthetic route for testing their anti-dengue protease inhibition.  ...  Thus, the synthesised BITs were tested for inhibitory activity against the recombinant dengue virus serotype-2 (DENV-2) NS2BNS3 protease.  ...  Acknowledgments: The assistance and support of Heike Oberwinkler and Melissa Zimniak in designing and executing the in-vitro studies are greatly acknowledged.  ... 
doi:10.3390/pathogens10040464 pmid:33921368 fatcat:aufujbzicre6xakbu63riirwvm

Computational approach to decipher cellular interactors and drug targets during co-infection of SARS-CoV-2, Dengue, and Chikungunya virus

Ritu Ghildiyal, Reema Gabrani
2021 VirusDisease  
The co-occurrence of the Dengue virus (DENV) and Chikungunya virus (CHIKV) has been into existence, but recently the co-infection of DENV and SARS-CoV-2 has been reported.  ...  In total, 17 interacting host proteins were identified showing association with envelope, structural, non-structural, and accessory proteins.  ...  Funding The research was funded by Council of Scientific and Industrial Research (CSIR) for providing financial support (ack. no. 113486/2K18/1).  ... 
doi:10.1007/s13337-021-00665-8 pmid:33723515 pmcid:PMC7945596 fatcat:jlkz664pzzczjavdn3uzje6gdm

Computer-Assisted and Data Driven Approaches for Surveillance, Drug Discovery, and Vaccine Design for the Zika Virus

Subhash C. Basak, Subhabrata Majumdar, Ashesh Nandy, Proyasha Roy, Tathagata Dutta, Marjan Vracko, Apurba K. Bhattacharjee
2019 Pharmaceuticals  
Modern technologies, including computational tools as well as experimental approaches, need to be harnessed fast and effectively in a coordinated manner in order to properly address such challenges.  ...  In this paper, based on our earlier research, we have proposed a four-pronged approach to tackle the emerging pathogens like ZIKV: (a) Epidemiological modelling of spread mechanisms of ZIKV; (b) assessment  ...  Importantly, three of these NS proteins, NS2B-NS3 protease, NS3 helicase, and NS5 methyltransferase are available with ligands, ATP and RNA in the data bank.  ... 
doi:10.3390/ph12040157 pmid:31623241 pmcid:PMC6958466 fatcat:unxtxxjpznazvcdphl7zacxdhu
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