Identification of potential Zika virus NS2B-NS3 protease inhibitors via docking, molecular dynamics and consensus scoring-based virtual screening

Bowen, Lucy; Li, Dennis J; Nola, Derek; Anderson, Marc O.; Heying, Michael; Groves, Adam; Eagon, Scott

doi:10.1007/s00894-019-4076-6

Cited by 13 publications

(9 citation statements)

References 48 publications

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“…The best ligand as observed from the result is ZINC ID:05220992 (named as C-992) which was used for experimental validation. Several reports showed that using idock score people screened inhibitor (idock score≤ -8 kcal/mol) molecules against various receptors and worked well as per experimental validation report [27,28]. In this context, our screened compound showing a better idock score and RF score (-10.17 kcal/mol, 6.22 pKd).…”

Section: Methodsmentioning

confidence: 54%

High throughput screening of a new fluorescent G-quadruplex ligand having telomerase inhibitory activity in human A549 cells

Ghosh¹,

De²,

Banerjee³

et al. 2021

Preprint

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Genome-wide analysis showed that putative G-quadruplex DNA structures are prevalent in the human genome. The presence of G-quadruplex structure in the telomere and promoter region of certain oncogenes inspired people to use G-quadruplex ligand as anti-cancer agents. G-quadruplex structures, stabilized by ligand at telomere are resolved by telomerase making the cancer cells resistant to G-quadruplex ligand. So, identification of a new G-quadruplex ligand having anti-telomerase activity would be a promising strategy for cancer therapy as about 85% of human cancers are telomerase positive. A set of the drug-like compounds were screened from the ZINC database randomly and 2284 ligands were chosen following Lipinski’s rule of five that were docked with five different G-quadruplex DNA sequences in idock. We screened 43 potential G-quadruplex binders using Z-score as a normalization scoring function. The compound (ZINC ID-05220992) gave the best score (average idock = −10.17 kcal/mol, average normalized idock = −3.42). We performed G4 FID assay, CD analysis to understand its binding with three different G-quadruplex DNA sequences, and checked its anti-telomerase activity in A549 cells using TRAP assay. We observed that this compound had an intrinsic fluorescence, capability to stain live cells with a blue fluorescence, and a specific affinity to only 22AG out of three different G-quadruplex DNA sequences under study. It showed cytotoxicity, good permeability to live cells, and a significant reduction of telomerase activity in human A549 cells at a very low dose. So, this compound has strong potential to be an anti-cancer drug.Graphical AbstractHighlightsA set of compounds were screened randomly by a High throughput method and Lipinski’s rule of five from ZINC database to identify potential G4-binders.The compound (ZINC ID-05220992) was screened after docking with five G-quadruplex DNAIt binds G-quadruplex DNA 22AG as detected by TO displacement and CD spectroscopy.It inhibits telomerase activity in A549 cells and also cytotoxic to this cell.It penetrates live A549 cell in culture and stains it with blue fluorescence

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Section: Methodsmentioning

confidence: 54%

High throughput screening of a new fluorescent G-quadruplex ligand having telomerase inhibitory activity in human A549 cells

Ghosh¹,

De²,

Banerjee³

et al. 2021

Preprint

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“…Furthermore, clozapine and chlorcyclizine are able to perform hydrogen bonds or hydrophobic interactions to Gly151 and Tyr161, respectively. These amino acids are considered as important for molecular recognition of the binding site of NS2B-NS3 Protease. , …”

Section: Resultsmentioning

confidence: 99%

“…This context has been encouraged the development of anti-ZIKV drugs. − Among ZIKV molecular targets able to suffer intervention by a drug, ZIKV nonstructural proteins such as NS2B-NS3 protease and NS5Methyltransferase have been highlighted due to their essential role for viral replication. Consequentially, both have been considered attractive molecular targets to the development of antiviral drugs. , …”

Section: Introductionmentioning

confidence: 99%

“…Consequentially, both have been considered attractive molecular targets to the development of antiviral drugs. 11,12 The ZIKV protease (NS2B-NS3pro) is a chymotrypsin-like serine-protease formed by association to hydrophilic region of NS2B anchored into endoplasmic reticulum (ER) membrane. Similar to other flaviviruses proteases, this two-component complex has a catalytic triad formed by His51-Asp75-Ser135.…”

Section: ■ Introductionmentioning

confidence: 99%

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Identification of Zika Virus NS2B-NS3 Protease Inhibitors by Structure-Based Virtual Screening and Drug Repurposing Approaches

Santos

Nunes

Lima

et al. 2019

J. Chem. Inf. Model.

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The NS2B-NS3 protease has been identified as an attractive target for drug development against Zika virus (ZIKV) and combined drug repurposing and structure-based virtual screening has improved the development of antiviral drugs. In this study, we performed a structurebased virtual screening of 1861 Food and Administration (FDA) approved drugs available in DrugBank by the selection and docking validation of crystal structure of ZIKV NS2B-NS3 protease (PDB ID 5H4I) using Glide and DOCK 6 software. The antihistaminic chlorcyclizine (Grid score −24.8 kcal/ mol) exhibited the most promising interaction with NS2B-NS3 protease in comparison to crystallography ligand (Grid score −15.6 kcal/mol) by interaction to Tyr161 by hydrophobic interactions in the binding site of NS2B-NS3 which is recognized as an important amino acid in substrate molecular recognition. Cytotoxicity and global antiviral activity assay in Vero cells by MTT method showed that chlorcyclizine reduced the ZIKV induced cytopathic effect (EC 50 of 69.0 ± 7.3 μM and SI = 1.9), and explicit molecular dynamics simulations implemented on a NAMD program indicated great stability of chlorcyclizine in protease binding site, suggesting the repurposing of chlorcyclizine as a promising finding in anti-ZIKV drug development.

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“…The IC 50 was 69.0 µM. Lucy et al identified potential ZIKV protease inhibitors via virtual screening [ 32 ]. It is still necessary to test that these compounds inhibit the ZIKV infection.…”

Section: Discussionmentioning

confidence: 99%

Structure-Based Virtual Screening: Identification of a Novel NS2B-NS3 Protease Inhibitor with Potent Antiviral Activity against Zika and Dengue Viruses

et al. 2021

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Zika virus (ZIKV), which is associated with severe diseases in humans, has spread rapidly and globally since its emergence. ZIKV and dengue virus (DENV) are closely related, and antibody-dependent enhancement (ADE) of infection between cocirculating ZIKV and DENV may exacerbate disease. Despite these serious threats, there are currently no approved antiviral drugs against ZIKV and DENV. The NS2B-NS3 viral protease is an attractive antiviral target because it plays a pivotal role in polyprotein cleavage, which is required for viral replication. Thus, we sought to identify novel inhibitors of the NS2B-NS3 protease. To that aim, we performed structure-based virtual screening using 467,000 structurally diverse chemical compounds. Then, a fluorescence-based protease inhibition assay was used to test whether the selected candidates inhibited ZIKV protease activity. Among the 123 candidate inhibitors selected from virtual screening, compound 1 significantly inhibited ZIKV NS2B-NS3 protease activity in vitro. In addition, compound 1 effectively inhibited ZIKV and DENV infection of human cells. Molecular docking analysis suggested that compound 1 binds to the NS2B-NS3 protease of ZIKV and DENV. Thus, compound 1 could be used as a new therapeutic option for the development of more potent antiviral drugs against both ZIKV and DENV, reducing the risks of ADE.

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Identification of potential Zika virus NS2B-NS3 protease inhibitors via docking, molecular dynamics and consensus scoring-based virtual screening

Cited by 13 publications

References 48 publications

High throughput screening of a new fluorescent G-quadruplex ligand having telomerase inhibitory activity in human A549 cells

High throughput screening of a new fluorescent G-quadruplex ligand having telomerase inhibitory activity in human A549 cells

Identification of Zika Virus NS2B-NS3 Protease Inhibitors by Structure-Based Virtual Screening and Drug Repurposing Approaches

Structure-Based Virtual Screening: Identification of a Novel NS2B-NS3 Protease Inhibitor with Potent Antiviral Activity against Zika and Dengue Viruses

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