Flavivirus Protease: An Antiviral Target

Tomar, Shailly; Mudgal, Rajat; Fatma, Benazir

doi:10.1016/b978-0-12-809712-0.00006-x

Cited by 5 publications

(3 citation statements)

References 101 publications

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“…We identified the targeted non-structural proteins (non-structural protein targets) (NS3, NS4A, and NS5) through literature analysis providing importance on the activity of proteins and their involvement in the life cycle of DENV-3 to be an antiviral drug target. 4 , 21 - 23 These 3 non-structural proteins were used to explore antiviral drugs as these non-structural proteins hold conserved regions and play an indispensable role at the replication stage of the life cycle of DENV-3.…”

Section: Methodsmentioning

confidence: 99%

S-Adenosyl-l-Homocysteine Exhibits Potential Antiviral Activity Against Dengue Virus Serotype-3 (DENV-3) in Bangladesh: A Viroinformatics-Based Approach

Shill

Jahan

Alam

et al. 2023

Bioinform Biol Insights

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Dengue outbreak is one of the concerning issues in Bangladesh due to the annual outbreak with the alarming number of death and infection. However, there is no effective antiviral drug available to treat dengue-infected patients. This study evaluated and screened antiviral drug candidates against dengue virus serotype 3 (DENV-3) through viroinformatics-based analyses. Since 2017, DENV-3 has been the predominant serotype in Bangladesh. We selected 3 non-structural proteins of DENV-3, named NS3, NS4A, and NS5, as antiviral targets. Protein modeling and validation were performed with VERIFY-3D, Ramachandran plotting, MolProbity, and PROCHECK. We found 4 drug-like compounds from DRUGBANK that can interact with these non-structural proteins of DENV-3. Then, the ADMET profile of these compounds was determined by admetSAR2, and molecular docking was performed with AutoDock, SWISSDOCK, PatchDock, and FireDock. Furthermore, they were subjected to molecular dynamics (MD) simulation study using the DESMOND module of MAESTRO academic version 2021-4 (force field OPLS_2005) to determine their solution’s stability in a predefined body environment. Two drug-like compounds named Guanosine-5’-Triphosphate (DB04137) and S-adenosyl-l-homocysteine (DB01752) were found to have an effective binding with these 3 proteins (binding energy > 33.47 KJ/mole). We found NS5 protein was stable and equilibrated in a 100 ns simulation run along with a negligible (<3Å) root-mean-square fluctuation value. The root-mean-square deviation value of the S-adenosyl-l-homocysteine-NS5 complex was less than 3Å, indicating stable binding between them. The global binding energy of S-adenosyl-l-homocysteine with NS5 was −40.52 KJ/mole as ∆G. Moreover, these 2 compounds mentioned above are non-carcinogenic according to their ADMET (chemical absorption, distribution, metabolism, excretion, and toxicity) profile (in silico). These outcomes suggest the suitability of S-adenosyl-l-homocysteine as a potential drug candidate for dengue drug discovery research.

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Section: Methodsmentioning

confidence: 99%

S-Adenosyl-l-Homocysteine Exhibits Potential Antiviral Activity Against Dengue Virus Serotype-3 (DENV-3) in Bangladesh: A Viroinformatics-Based Approach

Shill

Jahan

Alam

et al. 2023

Bioinform Biol Insights

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“…All conformations obtained from the k-means cluster analysis were used to search alternative druggable pockets, as these are the intermediate conformations that can be observed during the activation of NS2B/NS3. We excluded the obtained conformations from the MD simulation of NS3 without NS2B complex for the analysis because the flexible NS2B cofactor is essential for the activity of NS3 protease without which NS3 protease cannot fold properly to the functional active chymotrypsin-like conformation [43]. First, potential binding pockets of two conformations of the NS2B/NS3 complex were identified using the DoGSiteScorer program (https://proteins.plus (accessed on 3 August 2023)).…”

Section: Potential Druggable Pocketsmentioning

confidence: 99%

Structural Modifications Introduced by NS2B Cofactor Binding to the NS3 Protease of the Kyasanur Forest Disease Virus

Kandagalla

Kumbar

Novak

2023

IJMS

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Kyasanur Forest Disease virus (KFDV), a neglected human pathogenic virus, is a Flavivirus that causes severe hemorrhagic fever in humans. KFDV is transmitted to humans by the bite of the hard tick (Haemaphysalis spinigera), which acts as a reservoir of KFDV. The recent expansion of the endemic area of KFDV is of concern and requires the development of new preventive measures against KFDV. Currently, there is no antiviral therapy against KFDV, and the existing vaccine has limited efficacy. To develop a new antiviral therapy against KFDV, we focused on the nonstructural proteins NS2B and NS3 of KFDV, which are responsible for serine protease activity. Viral proteases have shown to be suitable therapeutic targets in the development of antiviral drugs against many diseases. However, success has been limited in flaviviruses, mainly because of the important features of the active site, which is flat and highly charged. In this context, the present study focuses on the dynamics of NS2B and NS3 to identify potential allosteric sites in the NS2B/NS3 protease of KDFV. To our knowledge, there are no reports on the dynamics of NS2B and NS3 in KFDV, and the crystal structure of the NS2B/NS3 protease of KFDV has not yet been solved. Overall, we created the structure of the NS2B/NS3 protease of KFDV using AlphaFold and performed molecular dynamics simulations with and without NS2B cofactor to investigate structural rearrangements due to cofactor binding and to identify alternative allosteric sites. The identified allosteric site is promising due to its geometric and physicochemical properties and druggability and can be used for new drug development. The applicability of the proposed allosteric binding sites was verified for the best-hit molecules from the virtual screening and MD simulations.

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“…The genome contains only one open reading frame (ORF) flanked by 5' and 3'untranslated regions (UTRs) that encodes a polyprotein. The translated polyprotein is directed into host endoplasmic reticulum (ER) membrane by signal sequences and cleaved by host protease into three structural proteins, a nucleocapsid protein (C protein), a precursor membrane glycoprotein (prM protein) and a glycosylated envelope protein (E protein), as well as seven non-structural (NS) proteins [15][16][17][18][19]. The C protein is responsible for encapsulation of the virus to protect the genetic material.…”

Section: Introductionmentioning

confidence: 99%

Computational Prediction of Multi-Epitopes Vaccine from Envelope E Protein against Louping Ill Virus via Reverse Vaccinology

2020

JCEI

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Louping ill disease is a zoonotic viral disease caused by louping ill virus in the genus Flavivirus. It belongs to the tick-borne flavivirus that is a part of the tick-borne encephalitis virus complex.The envelope E protein of louping ill virus is the major structural protein that plays an important role in membrane binding and inducing a protective immune response.The aim of the present study was to design multi epitopes vaccine from the envelope E glycoprotein against louping ill virus using immunoinformatic tools that elicited humoral and cellular immunity. Eighteen envelope E protein sequences were retrieved from NCBI and subjected to various immunoinformatics tools from IEDB to assess their conservancy, surface accessibility and antigenicity as promising epitopes against B cells. The binding affinity of the conserved predicted epitopes was analyzed against MHC-I and MHC-II alleles of the T cells. The predicted epitopes were further assessed for their population coverage. For B-cell 25, 18 and 12 epitopes were predicted as linear conserved epitopes, surface accessibility and antigenic respectively. However, nine epitopes overlapped all the B cell prediction tools. Among them three epitopes (205-TAEHLP-210,336-KPCR-339 and 349-SPDV-352) were proposed as B cell epitopes. For T cell, 75 epitopes were found to interact with MHC-I alleles. The epitopes 130-YVYDANKV-138and356-MLITPNPTI-364 were proposed as a peptide vaccine since they interacted with the highest number of MHC-1 alleles.Moreover a total of 195core epitopes were found to interact with MHC-II alleles. The core epitopes 130-YVYDANKV-138, 219-WFNDLALPW-227, 415-VIGEHAWDF-423 and 462-VALAWLGLN-470 interacted with higher number of MHC-II alleles and proposed as vaccine since they demonstrated high affinity to MHC-II alleles.The population coverage epitopes set for MHC-I and MHC-II alleles was 74.69% and 99.98%, respectively. While the epitopes set for all T cell, proposed epitopes was 100%. Nine epitopes were predicted eliciting B and T cells and proposed as vaccine candidates against louping ill virus. However, these proposed epitopes require clinical trials studies to ensure their efficacy as vaccine candidates.

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Flavivirus Protease: An Antiviral Target

Cited by 5 publications

References 101 publications

S-Adenosyl-l-Homocysteine Exhibits Potential Antiviral Activity Against Dengue Virus Serotype-3 (DENV-3) in Bangladesh: A Viroinformatics-Based Approach

S-Adenosyl-l-Homocysteine Exhibits Potential Antiviral Activity Against Dengue Virus Serotype-3 (DENV-3) in Bangladesh: A Viroinformatics-Based Approach

Structural Modifications Introduced by NS2B Cofactor Binding to the NS3 Protease of the Kyasanur Forest Disease Virus

Computational Prediction of Multi-Epitopes Vaccine from Envelope E Protein against Louping Ill Virus via Reverse Vaccinology

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