scholarly journals Screening of terpenoids as potential therapeutics against Zaire ebolavirus infection through pharmacophore-based drug design

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 1040
Author(s):  
Ade Hanna Natalia ◽  
Usman Sumo Friend Tambunan
Keyword(s):  
Molecular Docking ◽  
Drug Design ◽  
Molecular Interactions ◽  
Ebola Virus ◽  
Virus Disease ◽  
Docking Simulation ◽  
Host Cells ◽  
Virus Species ◽  
Docking Simulations ◽  
Zaire Ebolavirus

Backgroud: Ebola virus disease (EVD) has spread to various countries in the world and has caused many deaths. Five different virus species can cause EVD, but the most virulent is Zaire ebolavirus (EBOV). The genome of EBOV includes seven genes that encode proteins playing essential roles in the virus lifecycle. Among these proteins, VP24 plays a vital role in the inhibition of the host cells’ immune system. Therefore, VP24 is a potential target for EVD therapy. In the present study, a potential inhibitor of EBOV VP24 activity was identified through pharmacophore-based drug design. Methods: This research was a in silico study, using pharmacophore based molecular docking simulation to obtain inhibitor candidates. Result: Terpenoids were used as VP24 inhibitor candidates. In particular, 55,979 terpenoids were obtained from the PubChem database. An initial screening based on the toxicity prediction test was performed with DataWarrior software: 3,353 ligands were shown to have a favorable toxicity profile, but only 1,375 among them had suitable pharmacophore features. These ligands were used for pharmacophore-based rigid and flexible molecular docking simulations with PDB ID: 4M0Q, chosen as the crystal structure of EBOV VP24. Six ligands predicted to have strong molecular interactions with EBOV VP24 underwent pharmacological property analysis through various software packages, including DataWarrior, SwissADME, admetSAR, pkCSM, and Toxtree. Conclusions: Taxumairol V was identified as the best candidate for EVD drug therapy via EBOV VP24 inhibition based on its molecular properties, predicted molecular interactions with the target molecule, and predicted pharmacological properties.

scholarly journals Immunological Perspective for Ebola Virus Infection and Various Treatment Measures Taken to Fight the Disease

Pathogens ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 850
Author(s):  
Sahil Jain ◽  
Svetlana F. Khaiboullina ◽  
Manoj Baranwal
Keyword(s):  
Ebola Virus ◽  
Virus Disease ◽  
Cell Types ◽  
Host Cells ◽  
Humoral Immune ◽  
T Cell Apoptosis ◽  
Treatment Measures ◽  
Ebov Infection ◽  
Zaire Ebolavirus ◽  
Potential Factors

Ebolaviruses, discovered in 1976, belongs to the Filoviridae family, which also includes Marburg and Lloviu viruses. They are negative-stranded RNA viruses with six known species identified to date. Ebola virus (EBOV) is a member of Zaire ebolavirus species and can cause the Ebola virus disease (EVD), an emerging zoonotic disease that results in homeostatic imbalance and multi-organ failure. There are three EBOV outbreaks documented in the last six years resulting in significant morbidity (>32,000 cases) and mortality (>13,500 deaths). The potential factors contributing to the high infectivity of this virus include multiple entry mechanisms, susceptibility of the host cells, employment of multiple immune evasion mechanisms and rapid person-to-person transmission. EBOV infection leads to cytokine storm, disseminated intravascular coagulation, host T cell apoptosis as well as cell mediated and humoral immune response. In this review, a concise recap of cell types targeted by EBOV and EVD symptoms followed by detailed run-through of host innate and adaptive immune responses, virus-driven regulation and their combined effects contributing to the disease pathogenesis has been presented. At last, the vaccine and drug development initiatives as well as challenges related to the management of infection have been discussed.

scholarly journals Identification of Diaryl-Quinoline Compounds as Entry Inhibitors of Ebola Virus

Viruses ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 678 ◽  
Author(s):  
Qinghua Cui ◽  
Han Cheng ◽  
Rui Xiong ◽  
Gang Zhang ◽  
Ruikun Du ◽  
...  
Keyword(s):  
Drug Development ◽  
Ebola Virus ◽  
Virus Disease ◽  
Virus Entry ◽  
Surface Protein ◽  
Host Cells ◽  
Entry Inhibitor ◽  
Entry Inhibitors ◽  
Promising Target ◽  
Virus Entry Inhibitors

Ebola virus is the causative agent of Ebola virus disease in humans. The lethality of Ebola virus infection is about 50%, supporting the urgent need to develop anti-Ebola drugs. Glycoprotein (GP) is the only surface protein of the Ebola virus, which is functionally critical for the virus to attach and enter the host cells, and is a promising target for anti-Ebola virus drug development. In this study, using the recombinant HIV-1/Ebola pseudovirus platform we previously established, we evaluated a small molecule library containing various quinoline compounds for anti-Ebola virus entry inhibitors. Some of the quinoline compounds specifically inhibited the entry of the Ebola virus. Among them, compound SYL1712 was the most potent Ebola virus entry inhibitor with an IC50 of ~1 μM. The binding of SYL1712 to the vial glycoprotein was computationally modeled and was predicted to interact with specific residues of GP. We used the time of the addition assay to show that compound SYL1712 blocks Ebola GP-mediated entry. Finally, consistent with being an Ebola virus entry inhibitor, compound SYL1712 inhibited infectious Ebola virus replication in tissue culture under biosafety level 4 containment, with an IC50 of 2 μM. In conclusion, we identified several related molecules with a diaryl-quinoline scaffold as potential anti-EBOV entry inhibitors, which can be further optimized for anti-Ebola drug development.

scholarly journals Molecular Docking Study of Anthocyanidin Compounds Against Epidermal Growth Factor Receptor (EGFR) as Anti-Lung Cancer

2021 ◽  
Vol 8 (1) ◽  
pp. 8
Author(s):  
Riska Prasetiawati ◽  
Meilia Suherman ◽  
Benny Permana ◽  
Rahmawati Rahmawati
Keyword(s):  
Lung Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Molecular Docking ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Docking Simulation ◽  
Molecular Docking Study ◽  
Docking Simulations ◽  
Epidermal Growth

It is presumed that antiproliferative activity of anthocyanidin has interaction with Epidermal Growth Factor Receptor (EGFR) which has effect on lung cancer cell growth. This study aimed to observe the interaction between anthocyanidin and EGFR and to find out prediction, absorption, distribution activities as well as anthocyanidin toxicity compared to Gefitinib, an EGFR inhibitor. All test compounds were optimized with Autodock Tools®, then molecular docking simulations and predictions of absorption, distribution and toxicity were carried out. Malvidin was stated to meet the Lipinski's Rule of Five, indicating good bioavailability. Result of molecular docking simulation showed that malvidin had better affinity against EGFR than Gefitinib. Molecular docking visualization result showed that malvidin had interaction with amino acid residue such as Met793, Gln791, Leu718, Thr854, Asp855 and Lys745. Absorption and distribution predictions included percentage scores of Human Intestinal Absorption (HIA), human colon adenocarcinoma (Caco-2), and Plasma Protein Binding. Toxicity test revealed that malvidin was mutagenic compound but not carcinogenic one. The findings indicated that malvidin was potential to be an anti lung cancer candidate through EGFR inhibition.Keywords: Antiproliferative, Anthocyanidin, Epidermal Growth Factor Receptor, Molecular Docking

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

2020 ◽  
Vol 10 (1) ◽  
pp. 4929-4933
Keyword(s):  
Molecular Docking ◽  
Therapeutic Strategy ◽  
Docking Simulation ◽  
Drug Candidate ◽  
Synthetic Compounds ◽  
Molecular Docking Simulation ◽  
Docking Simulations ◽  
Lipinski’S Rule ◽  
Mercaptosuccinic Acid ◽  
Significant Public Health

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.

Drug design and molecular docking simulations of Polo-like kinase 1 inhibitors based on QSAR study

2020 ◽  
Vol 44 (48) ◽  
pp. 21134-21145
Author(s):  
Jianbo Tong ◽  
Tianhao Wang ◽  
Yi Feng
Keyword(s):  
Molecular Docking ◽  
Drug Design ◽  
Qsar Study ◽  
Docking Simulations ◽  
Modeling Study ◽  
Systematic Modeling

Computationally exploring novel potential Polo-like kinase 1 inhibitors using a systematic modeling study.

scholarly journals P300-mediated NEDD4 acetylation drives ebolavirus VP40 egress by enhancing NEDD4 ligase activity

2021 ◽  
Vol 17 (6) ◽  
pp. e1009616
Author(s):  
Linliang Zhang ◽  
Shixiong Zhou ◽  
Majuan Chen ◽  
Jie Yan ◽  
Yi Yang ◽  
...  
Keyword(s):  
Life Cycle ◽  
Matrix Protein ◽  
Ebola Virus ◽  
Regulatory Mechanism ◽  
Physiological Effect ◽  
Host Cells ◽  
Post Translational Modifications ◽  
Virus Life Cycle ◽  
The Matrix ◽  
Zaire Ebolavirus

The final stage of Ebola virus (EBOV) replication is budding from host cells, where the matrix protein VP40 is essential for driving this process. Many post-translational modifications such as ubiquitination are involved in VP40 egress, but acetylation has not been studied yet. Here, we characterize NEDD4 is acetylated at a conserved Lys667 mediated by the acetyltransferase P300 which drives VP40 egress process. Importantly, P300-mediated NEDD4 acetylation promotes NEDD4-VP40 interaction which enhances NEDD4 E3 ligase activity and is essential for the activation of VP40 ubiquitination and subsequent egress. Finally, we find that Zaire ebolavirus production is dramatically reduced in P300 knockout cell lines, suggesting that P300-mediated NEDD4 acetylation may have a physiological effect on Ebola virus life cycle. Thus, our study identifies an acetylation-dependent regulatory mechanism that governs VP40 ubiquitination and provides insights into how acetylation controls EBOV VP40 egress.

scholarly journals Molecular Docking Studies of Curcumin Analogues against SARS-CoV-2 Spike Protein

2021 ◽  
Author(s):  
Jéssica Nogueira ◽  
Flávia Verza ◽  
Felipe Nishimura ◽  
Umashankar Das ◽  
Ícaro Caruso ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Virus Disease ◽  
Etiologic Agent ◽  
Host Cells ◽  
Spike Protein ◽  
Therapeutic Effects ◽  
Host Cell Membrane ◽  
Curcumin Analogues

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is the etiologic agent of the current pandemic of corona virus disease 2019 (COVID-19) that has inflicted the loss of thousands of lives worldwide. The coronavirus surface spike (S) glycoprotein is a class I fusion with a S1 domain which is attached to the human angiotensin converting enzyme 2 (ACE2) receptor, and a S2 domain which enables fusion with the host cell membrane and internalization of the virus. Curcumin has been suggested as a potential drug to control inflammation and as a potential inhibitor of S protein, but its therapeutic effects are hampered by poor bioavailability. We performed a molecular docking and dynamic study using 94 curcumin analogues designed to have improved metabolic stability against the SARS-CoV-2 spike protein and compared their affinity with curcumin and other potential inhibitors. The docking analysis suggested that the S2 domain is the main target of these compounds and compound 2606 displayed a higher binding affinity (-9.6 kcal mol-1) than curcumin (-6.8 kcal mol-1) and the Food and Drug Administration (FDA) approved drug hydroxychloroquine (-6.3 kcal mol-1). Further additional validation in vitro and in vivo of these compounds against SARS-CoV-2 may provide insights into the development of a drug that prevents virus entry into host cells.

Inhibitory Effect of Sesamolin on Melanogenesis in B16F10 Cells Determined by In Vitro and Molecular Docking Analyses

2020 ◽  
Vol 21 (2) ◽  
pp. 169-178
Author(s):  
Seung-Hwa Baek ◽  
Myung-Gyun Kang ◽  
Daeui Park
Keyword(s):  
Molecular Docking ◽  
Competitive Inhibition ◽  
Docking Simulation ◽  
Melanoma Cells ◽  
Inhibition Mechanism ◽  
Dual Function ◽  
Dependent Manner ◽  
Related Factors ◽  
Docking Simulations

Background: Melanin protects the skin against the harmful effects of ultraviolet irradiation. However, melanin overproduction can result in several aesthetic problems, including melasma, freckles, age spots and chloasma. Therefore, development of anti-melanogenic agents is important for the prevention of serious hyperpigmentation diseases. Sesamolin is a lignan compound isolated from sesame seeds with several beneficial properties, including potential for melanin inhibition. Objective: The aim of this study was to evaluate the anti-melanogenic effect of sesamolin in cell culture in vitro and the underlying mechanism of inhibition using molecular docking simulation. Methods: Melanogenesis was induced by 3-isobutyl-1-methylxanthine in B16F10 melanoma cells, and the inhibitory effects of sesamolin were evaluated using zymography, a tyrosinase inhibitory activity assay, western blotting, and real-time reverse transcription-polymerase chain reaction analysis. Docking simulations between sesamolin and tyrosinase were performed using Autodock vina. Results: Sesamolin significantly inhibited the expression of melanogenesis-related factors tyrosinase, and tyrosinase-related proteins 1 and 2 at the mRNA and protein levels. Treatment of melanoma cells with 50 µM sesamolin demonstrated the strongest inhibition against intercellular tyrosinase and melanin synthesis without exerting cytotoxic effects. Sesamolin significantly reduced mushroom tyrosinase activity in a dose-dependent manner via a competitive inhibition mechanism. Tyrosinase docking simulations supported that sesamolin (-6.5 kcal/mol) bound to the active site of tyrosinase more strongly than the positive control (arbutin, -5.7 kcal/mol). Conclusion: Sesamolin could be developed as a melanogenesis inhibiting agent owing to its dual function in blocking the generation of melanogenesis-related enzymes and inhibiting the enzymatic response of tyrosinase.

Anti-Trypanosoma cruzi Activity and Molecular Docking Studies of 1Hpyrazolo[ 3, 4-b]pyridine Derivatives

2020 ◽  
Vol 17 (2) ◽  
pp. 184-191 ◽  
Author(s):  
Camilo Henrique da Silva Lima ◽  
Júlio César de Araujo Vanelis Soares ◽  
Joana Lucius de Sousa Ribeiro ◽  
Estela Maris Freitas Muri ◽  
Sérgio de Albuquerque ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Phenyl Group ◽  
Docking Simulation ◽  
Docking Studies ◽  
Pyridine Derivatives ◽  
Trypanocidal Activity ◽  
Docking Simulations ◽  
Cytotoxicity Assays ◽  
Activity Screening ◽  
Insight Into

Background: Untargeted studies led to the development of some pyrazolopyridine derivatives for the antiparasitic profile, particularly the derivatives containing the structural carbohydrazide subunit. In this work, we proceeded in the biological screening of 27 N’- (substitutedphenylmethylene)- 4-carbohydrazide-3-methyl-1-phenyl-1H-pyrazolo[3, 4-b]pyridine derivatives against T. cruzi as well as the cytotoxic evaluation. To obtain more information about the trypanocidal activity of this class of compounds, we carried out molecular docking simulations to get an insight into putative targets in T. cruzi. Methods: The assays were evaluated against both trypomastigote and amastigote forms of T. cruzi and cytotoxicity assays on LLCMK2 cells. The predominant conformational compounds were analyzed and molecular docking simulations performed. Results: The results from trypanocidal activity screening of this series showed that just the compounds with phenyl group at C-6 position exhibited activity and the N’-4-hydroxyphenylmethylene derivative presented the best profile against both trypomastigote and amastigote forms of T. cruzi. Docking simulation results showed that this compound has a binding affinity with both CYP51 and cruzain targets of T. cruzi. Conclusion: Our results indicate that the hydroxyl substituent at the N’-substituted-phenylmethylene moiety and the phenyl ring at C-6 of 1H-pyrazolo[3,4-b]pyridine system are relevant for the trypanocidal activity of this class of compounds. Also, docking simulations showed that activity presented can be related to more than one target of the parasite.

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