scholarly journals Virtual Screening of FDA Approved Drugs Library to Identify a Potential Inhibitor against NS2B-NS3 Protease of Yellow Fever Virus

2021 ◽  
pp. 177-186
Author(s):  
Hasanain Abdulhameed Odhar ◽  
Salam Waheed Ahjel ◽  
Ali A. Mohammed Ali Albeer ◽  
Ahmed Fadhil Hashim ◽  
Suhad Sami Humadi
Keyword(s):  
Virtual Screening ◽  
Yellow Fever ◽  
Active Site ◽  
Yellow Fever Virus ◽  
Fever Virus ◽  
Dynamics Simulation ◽  
Hemorrhagic Disease ◽  
Approved Drugs ◽  
Ns3 Protease ◽  
Fda Approved Drugs

Yellow fever is a neglected hemorrhagic disease with a high case fatality rate ranging between 25% and 50% for the hospitalized patients. Yellow fever disease is caused by a zoonotic pathogen known as yellow fever virus. This RNA virus is usually transmitted by mosquitos and it is considered endemic in the tropical regions of South America and Africa. Although an effective vaccine is available for yellow fever virus, no antiviral drug is yet licensed against the disease. Thus, yellow fever virus is still representing a re-emerging threat among unvaccinated individuals in endemic regions. The NS2B-NS3 protease seems to play an important role in yellow fever virus replication cycle. As such, the NS2B-NS3 protease may represent a potential target for structure-based drug design and discovery. In this direction, computational approaches like virtual screening can be utilized to hasten the design of novel antivirals and/ or repurposing an already FDA approved drugs. In this in silico study, an FDA approved drugs library was screened against NS2B-NS3 protease crystal of yellow fever virus. Then the best hits with least energy of binding and ability of hydrogen bonding with key residues of protease active site were then selected and submitted to molecular dynamics simulation. And throughout simulation interval, only Olsalazine was able to stay in close proximity to the active site of protease crystal with least average MM-PBSA binding energy as compared to Dantrolene, Belinostat and Linezolid. This indicates that Olsalazine may have the best capacity to bind to NS2B-NS3 protease and interfere with its activity.

scholarly journals Computational Screening of FDA Approved Drugs from ZINC Database for Potential Inhibitors of Zika Virus NS2B/NS3 Protease: A Molecular Docking and Dynamics Simulation Study

2021 ◽  
pp. 308-319
Author(s):  
Hasanain Abdulhameed Odhar ◽  
Salam Waheed Ahjel ◽  
Zanan Abdulhameed Odhar
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
Zika Virus ◽  
Computational Study ◽  
Dynamics Simulation ◽  
Computational Screening ◽  
Approved Drugs ◽  
Ns3 Protease ◽  
Fda Approved Drugs ◽  
Molecular Docking And Dynamics

Zika virus is a mosquito borne pathogen with a single strand RNA genome. Human infection with this virus is usually asymptomatic, however outbreaks reported in both Pacific region and Latin America have been associated with increase in frequency of microcephaly in newborns and fetuses of infected mothers. Also, the incidence of Guillain-Barré syndrome had also increased among adults with Zika virus infection. Currently, neither vaccine nor antiviral drug has been developed against Zika virus. Structure based virtual screening can be employed, through drug repurposing strategy, to accelerate the identification of potential anti-Zika virus candidates. As such, virtual screening of approved drugs against Zika virus NS2B/NS3 protease can help to recognize new hits capable of hindering viral ability to replicate and evade immune system of the host. In this computational study, we have screened 1615 FDA approved drugs against NS2B/NS3 protease enzyme of Zika virus by using both molecular docking and dynamics simulation. Our virtual screening results indicate that the anti-muscarinic agent Darifenacin and the anti-diarrheal agent Loperamide may have a promising capacity to inhibit Zika virus NS2B/NS3 protease. According to molecular docking and dynamics simulation, these two approved drugs have good binding capacity to NS2B/NS3 as reported by docking energy of binding and MM-PBSA binding energy. In addition, both Darifenacin and Loperamide were able to maintain close proximity to protease crystal throughout simulation period. However, invitro evaluation of these two drugs against Zika virus NS2B/NS3 protease is required to confirm these computational results.

scholarly journals Mulberrofuran G, a Potent Inhibitor of SPIKE Protein of SARS Corona Virus 2

2021 ◽  
Author(s):  
Fatemeh Sadat Hosseini ◽  
Mohammad Reza Motamedi
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
Active Site ◽  
Potential Role ◽  
Potent Inhibitor ◽  
Screening Method ◽  
Spike Protein ◽  
Treatment Agent ◽  
Approved Drugs ◽  
Fda Approved Drugs

Background: At the onset of the 2020 year, Coronavirus disease (COVID-19) has become a pandemic and infected many people worldwide. Despite all efforts, no cure was found for this infection. Bioinformatics and medicinal chemistry have a potential role in the primary consideration of drugs to treat this infection. With virtual screening and molecular docking, some potent compounds and medications can be found and modified and then applied to treat disease in the next steps. Methods: By virtual screening method and PRYX software, some Food and Drug Administration (FDA) approved drugs and natural compounds have been docked with the SPIKE protein of SARS-CoV-2. Some more potent agents have been selected, and then new structures are designed with better affinity than them. After that, we searched for the molecules with a similar structure to designed compounds to find the most potent compound to our target. Results: Because of the study of structures and affinities, mulberrofuran G was the most potent compound in this study. The compound has interacted strongly with residues in the probably active site of SPIKE. Conclusion: Mulberrofuran G can be a treatment agent candidate for COVID-19 because of its good affinity to SPIKE of the virus and inhibition of virus-cell adhesion and entrance.

scholarly journals Yellow fever virus NS3 protease: peptide-inhibition studies

2007 ◽  
Vol 88 (8) ◽  
pp. 2223-2227 ◽  
Author(s):  
Kristina Löhr ◽  
John E. Knox ◽  
Wai Yee Phong ◽  
Ngai Ling Ma ◽  
Zheng Yin ◽  
...  
Keyword(s):  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Homology Model ◽  
Enzymic Activity ◽  
Fever Virus ◽  
Catalytically Active ◽  
Relationship Of ◽  
Ns3 Protease ◽  
Inhibition Studies ◽  
Factor Sequence

A recombinant form of yellow fever virus (YFV) NS3 protease, linked via a nonapeptide to the minimal NS2B co-factor sequence (CF40-gly-NS3pro190), was expressed in Escherichia coli and shown to be catalytically active. It efficiently cleaved the fluorogenic tetrapeptide substrate Bz-norleucine-lysine-arginine-arginine-AMC, which was previously optimized for dengue virus NS2B/3 protease. A series of small peptidic inhibitors based on this substrate sequence readily inhibited its enzymic activity. To understand the structure–activity relationship of the inhibitors, they were docked into a homology model of the YFV NS2B/NS3 protease structure. The results revealed that the P1 and P2 positions are most important for inhibitor binding, whilst the P3 and P4 positions have much less effect. These findings indicate that the characteristics of YFV protease are very similar to those reported for dengue and West Nile virus proteases, and suggest that pan-flavivirus NS3 protease drugs may be developed for flaviviral diseases.

scholarly journals Repurposing of FDA approved drugs targeting Main protease MPro for SARS-CoV-2

2020 ◽  
Author(s):  
Suryakant Tiwari ◽  
Raghav Jain ◽  
Indrani Banerjee
Keyword(s):  
Drug Discovery ◽  
Virtual Screening ◽  
Active Site ◽  
Ligand Docking ◽  
Kcal Mole ◽  
Main Protease ◽  
Alternative Approach ◽  
Repurposed Drugs ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract SARS-CoV-2 is one of the greatest pandemics in the history. There is no medicine or vaccine yet discovered to control the outbreak. The paper deals with repurposing existing drugs to control the outbreak of SARS-CoV-2 virus.Ten FDA-approved drugs namely Indinavir, Nelfinavir, Letermovir, Irinotecan, Elbasvir, Saquinavir, Darunavir, Raltegravir, Atazanavir and Amprenavir were studied. In silico methods for virtual screening of protein-ligand docking of these drugs against SARS-CoV-2 MPro was performed. The binding efficiency of the drugs against viral main protease MPro was significantly high to inhibit SARS-CoV-2.The results confirmed that Atazanavir, Nelfinavir, and Letermovir not only occupied the active site of Mpro but also showed increased binding affinity (-10.36 kcal/mole, -9.47 kcal/mole and -9.43 kcal/mole) even more than of control drugs of Lopinavir (-8.71 kcal/mole) and Ritonavir (-8.08 kcal/mole). These repurposed drugs can be used in combination or individually as an alternative approach for rapid drug discovery against SARS-CoV-2

Structural characterization and polymorphism analysis of the NS2B-NS3 protease from the 2017 Brazilian circulating strain of Yellow Fever virus

2020 ◽  
Vol 1864 (4) ◽  
pp. 129521 ◽  
Author(s):  
Gabriela Dias Noske ◽  
Victor Oliveira Gawriljuk ◽  
Rafaela Sachetto Fernandes ◽  
Nathalia Dias Furtado ◽  
Myrna Cristina Bonaldo ◽  
...  
Keyword(s):  
Yellow Fever ◽  
Structural Characterization ◽  
Yellow Fever Virus ◽  
Fever Virus ◽  
Polymorphism Analysis ◽  
Ns3 Protease

scholarly journals Yellow fever virus NS2B/NS3 protease: Hydrolytic Properties and Substrate Specificity

2011 ◽  
Vol 407 (4) ◽  
pp. 640-644 ◽  
Author(s):  
Marcia Y. Kondo ◽  
Lilian C.G. Oliveira ◽  
Debora N. Okamoto ◽  
Marina R.T. de Araujo ◽  
Claudia N. Duarte dos Santos ◽  
...  
Keyword(s):  
Substrate Specificity ◽  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Fever Virus ◽  
Ns3 Protease

scholarly journals Yellow fever virus NS2B–NS3 protease: characterization of charged-to-alanine mutant and revertant viruses and analysis of polyprotein-cleavage activities

2005 ◽  
Vol 86 (5) ◽  
pp. 1403-1413 ◽  
Author(s):  
Thomas J. Chambers ◽  
Deborah A. Droll ◽  
Yujia Tang ◽  
Yan Liang ◽  
Vannakambadi K. Ganesh ◽  
...  
Keyword(s):  
Cell Culture ◽  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Fever Virus ◽  
Plaque Size ◽  
Protease Domain ◽  
Small Plaque ◽  
Cleavage Activity ◽  
Cellular Expression ◽  
Ns3 Protease

A series of 46 charged-to-alanine mutations in the yellow fever virus NS2B–NS3 protease, previously characterized in cell-free and transient cellular expression systems, was tested for their effects on virus recovery. Four distinct plaque phenotypes were observed in cell culture: parental plaque-size (13 mutants), reduced plaque-size (17 mutants), small plaque-size (8 mutants) and no plaque-formation (8 mutants). No mutants displayed any temperature sensitivity based on recovery of virus after RNA transfection at 32 versus 37 °C. Most small plaque-mutants were defective in growth efficiency compared with parental virus. However not all small plaque-mutants had defective 2B/3 cleavage, with some showing selective defects at other non-structural protein cleavage sites. Revertant viruses were recovered for six mutations that caused reduced plaque sizes. Same-site and second-site mutations occurred in NS2B, and one second-site mutation occurred in the NS3 protease domain. Some reversion mutations ameliorated defects in cleavage activity and plaque size caused by the original mutation. These data indicate that certain mutations that reduce NS2B–NS3 protease cleavage activity cause growth restriction of yellow fever virus in cell culture. However, for at least two mutations, processing defects other than impaired cleavage activity at the 2B/3 site may account for the mutant phenotype. The existence of reversion mutations primarily in NS2B rather than NS3, suggests that the protease domain is less tolerant of structural perturbation compared with the NS2B protein.

scholarly journals A Novel Benzodiazepine Compound Inhibits Yellow Fever Virus Infection by Specifically Targeting NS4B Protein

2016 ◽  
Vol 90 (23) ◽  
pp. 10774-10788 ◽  
Author(s):  
Fang Guo ◽  
Shuo Wu ◽  
Justin Julander ◽  
Julia Ma ◽  
Xuexiang Zhang ◽  
...  
Keyword(s):  
Amino Acid ◽  
Virus Infection ◽  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Antiviral Treatment ◽  
Fever Virus ◽  
Structural Basis ◽  
Hemorrhagic Disease ◽  
Highly Effective ◽  
Ns4b Protein

ABSTRACT Although a highly effective vaccine is available, the number of yellow fever cases has increased over the past 2 decades, which highlights the pressing need for antiviral therapeutics. In a high-throughput screening campaign, we identified an acetic acid benzodiazepine (BDAA) compound which potently inhibits yellow fever virus (YFV). Interestingly, while treatment of YFV-infected cultures with 2 μM BDAA reduced the virion production by greater than 2 logs, the compound was not active against 21 other viruses from 14 different viral families. Selection and genetic analysis of drug-resistant viruses revealed that replacement of the proline at amino acid 219 (P219) of the nonstructural protein 4B (NS4B) with serine, threonine, or alanine conferred YFV with resistance to BDAA without apparent loss of replication fitness in cultured mammalian cells. However, replacement of P219 with glycine conferred BDAA resistance with significant loss of replication ability. Bioinformatics analysis predicts that the P219 amino acid is localized at the endoplasmic reticulum lumen side of the fifth putative transmembrane domain of NS4B, and the mutation may render the viral protein incapable of interacting with BDAA. Our studies thus revealed an important role and the structural basis for the NS4B protein in supporting YFV replication. Moreover, in YFV-infected hamsters, oral administration of BDAA protected 90% of the animals from death, significantly reduced viral load by greater than 2 logs, and attenuated virus infection-induced liver injury and body weight loss. The encouraging preclinical results thus warrant further development of BDAA or its derivatives as antiviral agents to treat yellow fever. IMPORTANCE Yellow fever is an acute viral hemorrhagic disease which threatens approximately 1 billion people living in tropical areas of Africa and Latin America. Although a highly effective yellow fever vaccine has been available for more than 7 decades, the low vaccination rate fails to prevent outbreaks in at-risk regions. It has been estimated that up to 1.7 million YFV infections occur in Africa each year, resulting in 29,000 to 60,000 deaths. Thus far, there is no specific antiviral treatment for yellow fever. To cope with this medical challenge, we identified a benzodiazepine compound that selectively inhibits YFV by targeting the viral NS4B protein. To our knowledge, this is the first report demonstrating in vivo safety and antiviral efficacy of a YFV NS4B inhibitor in an animal model. We have thus reached a critical milestone toward the development of specific antiviral therapeutics for clinical management of yellow fever.

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