NS3 protease from flavivirus as a target for designing antiviral inhibitors against dengue virus

Natarajan, Satheesh

doi:10.1590/s1415-47572010000200002

Cited by 39 publications

(33 citation statements)

References 40 publications

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“…The His51-Asp75-Ser135 catalytic triad together with Gly151 are important residues present in the oxyanion pocket. 6,10 The RMSD value is 0.80 Å for the overlap of the α-carbons of the NS2B-NS3pro complex obtained from 2FOM (DENV-2 without ligand), 2FP7, 6 and the threedimensional model constructed for DENV-2 ( Figure 3). This value indicates a good superposition between the 3D residues are the most favored and allowed conformations, respectively.…”

Section: Comparative Modelingmentioning

confidence: 99%

“…Some of these residues, such as His51, Asp75 and Ser135, are directly related to enzymatic activity. 6,10,12 Previously, the residues Gly151 and Try161 have been described to be being important in recognizing inhibitors directed to this receptor. The C−O Ser135 distance, which involves the carbon atom of the aldehyde group near the hydroxyl group of Ser135, is believed to be an important moiety to enable the catalytic activity of serine proteases.…”

Section: Molecular Dockingmentioning

confidence: 99%

“…6,8 Its catalytic mechanism involves the nucleophilic attack of the oxygen from the serine hydroxyl group and the electrophilic carbon of the peptide bond to be cleaved. 6,[9][10][11] Erbel et al 6 identified important residues for inhibitor recognition in NS3pro such as Gly151, Gly153 and Tyr161. Regarding the organization of the flaviviral active site, Aleshin et al 12 demonstrated that a precise spatial arrangement is required to enhancehole'' is stabilized by Ser hydroxyl H-bonds to the His imidazole, which in turn H-bonds to the Asp carboxyl group.…”

Section: Introductionmentioning

confidence: 99%

“…12 Consequently, a tetrahedral intermediate is formed and stabilized by hydrogen bonds involving Gly151 and Ser135, which comprise the oxyanion pocket. 10 Thus, an inhibitor that is able to interact with these amino acid residues represents a potential candidate for the inhibition of the serine protease. The positions of the inhibitor P1, P2, P3 and P4 are related to the pockets S1, S2, S3 and S4 in this receptor, respectively.…”

Section: Introductionmentioning

confidence: 99%

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Docking and QM/MM Studies of NS2B-NS3pro Inhibitors: a Molecular Target against the Dengue Virus

Godói¹,

Lima²,

Comar³

et al. 2016

J. Braz. Chem. Soc.

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Dengue virus (DENV) has been characterized as having great clinical importance in the world, as there is no specific treatment against this virus. The NS2B-NS3pro complex is essential for the replication and maturation of DENV and is a potential pharmacological target. The present study aims to evaluate and understand the interactions and affinities (via molecular docking/AutoDock Vina) of 16 peptidomimetic derivatives applied to a NS2B-NS3pro DENV-2 complex constructed by homology modeling (via SWISS-MODEL). Two compounds were selected as potential inhibitors of this protein complex. In addition, these compounds possess important interactions involving Ser135, Gly169 and Tyr161, which have been described previously to be fundamental to the recognition of inhibitors directed to this receptor. Thus, the involvement of these residues is significant pharmacologically because they may contribute to the inhibitory action of this molecular target against DENV.Keywords: dengue, inhibitors, NS2B-NS3pro, molecular modeling IntroductionDengue fever affects approximately 390 million people annually, with higher prevalence in tropical and subtropical regions.1 Dengue virus (DENV) belongs to the genus Flavivirus and Flaviviridae families and is transmitted by the bite from female mosquitoes of the genus Aedes and species A. albopictus and A. aegypti.2 Currently, there is no specific therapy available against DENV; however, palliative treatments to circumvent symptoms caused by the disease are available. DENV has four antigenically distinct serotypes (i.e., DENV1-4), which makes it difficult to develop an effective vaccine. 2-4The viral RNA encodes 10,173 nucleotides that are translated into a polyprotein. This protein is then cleaved by viral and cellular proteases, culminating in the release of three structural proteins (i.e., capsid (C), precursor membrane protein (prM) and envelope (E)) and seven nonstructural proteins (i.e., NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5). 2,5 The serine protease called NS2B-NS3pro DENV has considerable genetic similarity with the analogous West Nile virus (WNV) protease. 6 This protease complex is directly related to replication and maturation of the virus, and it thus represents a promising molecular template for the treatment of these two pathogens. [5][6][7] The N-terminal region of NS2B-NS3pro has 187 amino acids and the catalytic triad His51-Asp75-Ser135 constitutes the active domain of the serine protease, which is essential for cleavage of the viral polyprotein. 6,8 Its catalytic mechanism involves the nucleophilic attack of the oxygen from the serine hydroxyl group and the electrophilic carbon of the peptide bond to be cleaved. 6,[9][10][11] Erbel et al. 6 identified important residues for inhibitor recognition in NS3pro such as Gly151, Gly153 and Tyr161. Regarding the organization of the flaviviral active site, Aleshin et al. 12 demonstrated that a precise spatial arrangement is required to enhance the nucleophilicity of the serine hydroxyl group present in the His-Asp-Ser catalytic t...

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Section: Comparative Modelingmentioning

confidence: 99%

Section: Molecular Dockingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Docking and QM/MM Studies of NS2B-NS3pro Inhibitors: a Molecular Target against the Dengue Virus

Godói¹,

Lima²,

Comar³

et al. 2016

J. Braz. Chem. Soc.

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“…DENV has also emerged as an increasing fitness problem in the world for which no specialized drug is available in the market. The non-structural protein NS3 protease of DENV has already been recognized as a potential therapeutic target for the discovery and development of novel antiviral agents against DENV infection [8,17,22,23,36,37]. NS3 molecule of DENV is comprised of a protease (NS3pro) and a helicase (NS3hel) domain, where the NS3pro domain relies on a cofactor, NS2B for their catalytic action and serves as a center for the assembly of the DENV replication complex and also modulates viral pathogenesis and the host immune response [4,6,11,18,19].…”

Section: Introductionmentioning

confidence: 99%

Identification of new potent inhibitors of dengue virus NS3 protease from traditional Chinese medicine database

et al. 2016

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Dengue virus (DENV) has emerged as an increasing fitness problem in the world for which no specialized drug is available. The non-structural protein NS3 protease of DENV has already been recognized as a potential therapeutic target for the discovery and development of novel antiviral agents against DENV infections. In this study, we employed the virtual screening technique to explore the potent inhibitors of DENV NS2B/NS3pro from Traditional Chinese Medicine (TCM) database. Total 200 inhibitors from TCM against DENV NS3pro were screened and only five TCM compounds like eriodictyol 7-O-glucuronide, luteolin 8-C-beta-glucopyranoside, (-)-epicatechin-3-O-gallate, 6-O-trans-p-coumaroylgeniposide and luteolin-7-O-glucoside were selected for further analysis which showed binding energies, -7.000, -7.380, -7.380, -7.440 and -7.440 kcal/mol, respectively. The findings of this study suggest that these five TCM compounds can be considered as potent inhibitors for DENV NS2B/NS3pro for the development of anti-dengue drugs.

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Structure‐based pharmacophore modeling, virtual screening approaches to identifying the potent hepatitis C viral protease and polymerase novel inhibitors

Venkatesan

Dhanabalan

Saravanakumar

et al. 2022

J of Cellular Biochemistry

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Hepatitis C is an infectious disease that leads to acute and chronic liver illnesses. Currently, there are no effective vaccines against this deadly virus. Direct acting antiviral (DAA) drugs are given in the combination with ribavirin and pegylated interferon which lead to adverse effects. Through in silico analysis, the structure‐based docking study was performed against NS3/4A protease and NS5B polymerase proteins of HCV. In the current study, multiple e‐pharmacophore‐based virtual screening methods such as HTVS, SP, and XP were carried out to screen natural compounds and enamine databases. Our result outcomes revealed that CID AE‐848/13196185 and CID AE‐848/36959205 compounds show good binding interactions with protease protein. In addition, CID 15081408 and CID 173568 show better binding interactions with the polymerase protein. Further to validate the docking results, we performed molecular dynamics simulation for the top hit compounds bound with protease and polymerase proteins to illustrate conformational differences in the stability compared with the active site of the cocrystal inhibitor. Thus, the current study emphasizes these compounds could be an effective drug to treat HCV.

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NS3 protease from flavivirus as a target for designing antiviral inhibitors against dengue virus

Cited by 39 publications

References 40 publications

Docking and QM/MM Studies of NS2B-NS3pro Inhibitors: a Molecular Target against the Dengue Virus

Docking and QM/MM Studies of NS2B-NS3pro Inhibitors: a Molecular Target against the Dengue Virus

Identification of new potent inhibitors of dengue virus NS3 protease from traditional Chinese medicine database

Structure‐based pharmacophore modeling, virtual screening approaches to identifying the potent hepatitis C viral protease and polymerase novel inhibitors

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