Modification of<i>S</i>-Adenosyl-<scp>l</scp>-Homocysteine as Inhibitor of Nonstructural Protein 5 Methyltransferase Dengue Virus Through Molecular Docking and Molecular Dynamics Simulation

Tambunan, Usman Sumo Friend; Nasution, Mochammad Arfin Fardiansyah; Azhima, Fauziah; Parikesit, Arli Aditya; Toepak, Erwin Prasetya; Idrus, Syarifuddin; Kerami, Djati

doi:10.1177/1177392817701726

Cited by 23 publications

(12 citation statements)

References 57 publications

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“…During the process of methylation, MTase converts SAM as the methyl donor into SAH [ 21 , 22 ], and this process is an important replication activity. The SAM/SAH binding site on MTase has been proposed as a potential target for anti-flavivirus agents in both DENV [ 23 ] and Zika virus (ZIKV) [ 24 ]. Thus, the binding of cordycepin to the SAM/SAH binding site on MTase may inhibit DENV RNA replication.…”

Section: Discussionmentioning

confidence: 99%

Cordycepin Inhibits Virus Replication in Dengue Virus-Infected Vero Cells

et al. 2021

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Dengue virus (DENV) infection causes mild to severe illness in humans that can lead to fatality in severe cases. Currently, no specific drug is available for the treatment of DENV infection. Thus, the development of an anti-DENV drug is urgently required. Cordycepin (3′-deoxyadenosine), which is a major bioactive compound in Cordyceps (ascomycete) fungus that has been used for centuries in Chinese traditional medicine, was reported to exhibit antiviral activity. However, the anti-DENV activity of cordycepin is unknown. We hypothesized that cordycepin exerts anti-DENV activity and that, as an adenosine derivative, it inhibits DENV replication. To test this hypothesis, we investigated the anti-DENV activity of cordycepin in DENV-infected Vero cells. Cordycepin treatment significantly decreased DENV protein at a half-maximal effective concentration (EC50) of 26.94 μM. Moreover, DENV RNA was dramatically decreased in cordycepin-treated Vero cells, indicating its effectiveness in inhibiting viral RNA replication. Via in silico molecular docking, the binding of cordycepin to DENV non-structural protein 5 (NS5), which is an important enzyme for RNA synthesis, at both the methyltransferase (MTase) and RNA-dependent RNA polymerase (RdRp) domains, was predicted. The results of this study demonstrate that cordycepin is able to inhibit DENV replication, which portends its potential as an anti-dengue therapy.

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Section: Discussionmentioning

confidence: 99%

Cordycepin Inhibits Virus Replication in Dengue Virus-Infected Vero Cells

et al. 2021

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“…In another study, Shanmugam and colleagues also identified, [2-(4-carbamoylpiperidin-1-yl)-2-oxoethyl] 8-(1,3-benzothiazol-2-yl) naphthalene-1-carboxylate as a potent dengue viral polymerase inhibitor by maintaining the same simulation condition from the previous study [60]. Most of the inhibitors were identified through an MD simulation against viral replication proteins, such as nonstructural protein 3 (NS3), NS5 methyltransferase, and also envelope protein (E) [58][59][60][61][62][63][64]. Currently, 18 million compounds were virtually-screened against dengue replication protein NS3, where the top five compounds have shown strong predicted binding affinity for the important catalytic residues of NS3 [65].…”

Section: Gclmentioning

confidence: 99%

Virtual Screening for Potential Inhibitors of Human Hexokinase II for the Development of Anti-Dengue Therapeutics

Tanbin

Fuad

Hamid

2020

BioTech

108

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Dengue fever, which is a disease caused by the dengue virus (DENV), is a major unsolved issue in many tropical and sub-tropical regions of the world. The absence of treatment that effectively prevent further viral propagation inside the human’s body resulted in a high number of deaths globally each year. Thus, novel anti-dengue therapies are required for effective treatment. Human hexokinase II (HKII), which is the first enzyme in the glycolytic pathway, is an important drug target due to its significant impact on viral replication and survival in host cells. In this study, 23.1 million compounds were computationally-screened against HKII using the Ultrafast Shape Recognition with a CREDO Atom Types (USRCAT) algorithm. In total, 300 compounds with the highest similarity scores relative to three reference molecules, known as Alpha-D-glucose (GLC), Beta-D-glucose-6-phosphate (BG6), and 2-deoxyglucose (2DG), were aligned. Of these 300 compounds, 165 were chosen for further structure-based screening, based on their similarity scores, ADME analysis, the Lipinski’s Rule of Five, and virtual toxicity test results. The selected analogues were subsequently docked against each domain of the HKII structure (PDB ID: 2NZT) using AutoDock Vina programme. The three top-ranked compounds for each query were then selected from the docking results based on their binding energy, the number of hydrogen bonds formed, and the specific catalytic residues. The best docking results for each analogue were observed for the C-terminus of Chain B. The top-ranked analogues of GLC, compound 10, compound 26, and compound 58, showed predicted binding energies of −7.2, −7.0, and −6.10 kcal/mol and 7, 5, and 2 hydrogen bonds, respectively. The analogues of BG6, compound 30, compound 36, and compound 38, showed predicted binding energies of −7.8, −7.4, and −7.0 kcal/mol and 11, 9, and 5 hydrogen bonds, while the top three analogues of 2DG, known as compound 1, compound 4, and compound 31, showed predicted binding energies of −6.8, −6.3, and −6.3 kcal/mol and 4, 3, and 1 hydrogen bonds, sequentially. The highest-ranked compounds in the docking analysis were then selected for molecular dynamics simulation, where compound 10, compound 30, and compound 1, which are the analogues of GLC, BG6, and 2DG, have shown strong protein-ligand stability with an RMSD value of ±5.0 A° with a 5 H bond, ±4.0 A° with an 8 H bond, and ±0.5 A° with a 2 H bond, respectively, compared to the reference molecules throughout the 20 ns simulation time. Therefore, by using the computational studies, we proposed novel compounds, which may act as potential drugs against DENV by inhibiting HKII’s activity.

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“…Its potential also can be determined through the score computed by software. As a result, through years, molecular docking simulation as part of computational drug delivery has developed significantly and become a crucial part of a new compound as a potential drug [13,19]. However, the molecular docking simulation may lead to false results as the rigid receptor docking employed in molecular docking simulation is not resembling the real characteristic of the receptor.…”

Section: Molecular Docking Simulations Of Ligandmentioning

confidence: 99%

“…One example of CADD is molecular docking simulation [12]. Studies describe molecular docking simulation as a study simulation to predict the conformation and affinity of ligands with a receptor [13,14]. Through various parameters such as the binding energy of ligand-receptor and root mean square deviation (RMSD), molecular docking simulation is employed [15].…”

Section: Introductionmentioning

confidence: 99%

Discovery of GPX4 inhibitor by molecular docking simulation as a potential ferroptosis inducer

Fatonah

Tambunan²,

Pamungkas

et al. 2020

Biointerface Res Appl Chem

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As one of the most complex diseases in the world, cancer continues as one of the significant public health problems. It was recorded by 2014 that cancer caused 1,551,000 death in Indonesia. One type of programmed cell death (PCD) that played a role in cancer cell treatment is Ferroptosis. Ferroptosis is PCD on iron and characterized by the inactivation of glutathione-dependent peroxidase (GPx4). In this research, a new therapeutic strategy for cancer was developed through the computational approach on synthetic compounds to discover its potential as an inhibitor of GPx4. About 688 compounds derivative from mercaptosuccinic acid acquired from the Zinc15 database. These compounds screened through the Lipinski’s Rule of Three and pharmacological prediction to eliminate ligands with undesired molecular properties. After that, the ligands underwent both rigid and flexible molecular docking simulations to predict their inhibition activity toward GPx4. From molecular docking simulation, (2S)-2-[(Z)-3-phenylprop-2-enyl]sulfanylbutanedioic acid show favorable characteristics as a drug candidate.

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Modification ofS-Adenosyl-l-Homocysteine as Inhibitor of Nonstructural Protein 5 Methyltransferase Dengue Virus Through Molecular Docking and Molecular Dynamics Simulation

Cited by 23 publications

References 57 publications

Cordycepin Inhibits Virus Replication in Dengue Virus-Infected Vero Cells

Cordycepin Inhibits Virus Replication in Dengue Virus-Infected Vero Cells

Virtual Screening for Potential Inhibitors of Human Hexokinase II for the Development of Anti-Dengue Therapeutics

Discovery of GPX4 inhibitor by molecular docking simulation as a potential ferroptosis inducer

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