In silico study on anti-Chikungunya virus activity of hesperetin

BackgroundThe re-emerging,Aedes spp.transmitted Chikungunya virus (CHIKV) has recently caused large outbreaks in a wide geographical distribution of the world including countries in Europe and America. Though fatalities associated with this self-remitting disease were rarely reported, quality of patients’ lives have been severely diminished by polyarthralgia recurrence. Neither effective antiviral treatment nor vaccines are available for CHIKV. Our previous in vitro screening showed that hesperetin, a bioflavonoid exhibits inhibitory effect on the virus intracellular replication. Here, we present a study using the computational approach to identify possible target proteins for future mechanistic studies of hesperetin.Methods3D structures of CHIKV nsP2 (3TRK) and nsP3 (3GPG) were retrieved from Protein Data Bank (PDB), whereas nsP1, nsP4 and cellular factor SPK2 were modeled using Iterative Threading Assembly Refinement (I-TASSER) server based on respective amino acids sequence. We performed molecular docking on hesperetin against all four CHIKV non-structural proteins and SPK2. Proteins preparation and subsequent molecular docking were performed using Discovery Studio 2.5 and AutoDock Vina 1.5.6. The Lipinski’s values of the ligand were computed and compared with the available data from PubChem. Two non-structural proteins with crystal structures 3GPG and 3TRK in complexed with hesperetin, demonstrated favorable free energy of binding from the docking study, were further explored using molecular dynamics (MD) simulations.ResultsWe observed that hesperetin interacts with different types of proteins involving hydrogen bonds, pi-pi effects, pi-cation bonding and pi-sigma interactions with varying binding energies. Among all five tested proteins, our compound has the highest binding affinity with 3GPG at −8.5 kcal/mol. The ligand used in this study also matches the Lipinski’s rule of five in addition to exhibiting closely similar properties with that of in PubChem. The docking simulation was performed to obtain a first guess of the binding structure of hesperetin complex and subsequently analysed by MD simulations to assess the reliability of the docking results. Root mean square deviation (RMSD) of the simulated systems from MD simulations indicated that the hesperetin complex remains stable within the simulation timescale.DiscussionThe ligand’s tendencies of binding to the important proteins for CHIKV replication were consistent with our previous in vitro screening which showed its efficacy in blocking the virus intracellular replication. NsP3 serves as the highest potential target protein for the compound’s inhibitory effect, while it is interesting to highlight the possibility of interrupting CHIKV replication via interaction with host cellular factor. By complying the Lipinski’s rule of five, hesperetin exhibits drug-like properties which projects its potential as a therapeutic option for CHIKV infection.

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An Analysis Based on Molecular Docking and Molecular Dynamics Simulation Study of Bromelain as Anti-SARS-CoV-2 Variants

Frontiers in Pharmacology ◽

10.3389/fphar.2021.717757 ◽

2021 ◽

Vol 12 ◽

Cited By ~ 1

Author(s):

Trina Ekawati Tallei ◽

Fatimawali ◽

Afriza Yelnetty ◽

Rinaldi Idroes ◽

Diah Kusumawaty ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Molecular Dynamics Simulation ◽

Three Dimensional ◽

Md Simulations ◽

Inhibitory Effect ◽

Dynamics Simulation ◽

Novel Coronavirus

The rapid spread of a novel coronavirus known as SARS-CoV-2 has compelled the entire world to seek ways to weaken this virus, prevent its spread and also eliminate it. However, no drug has been approved to treat COVID-19. Furthermore, the receptor-binding domain (RBD) on this viral spike protein, as well as several other important parts of this virus, have recently undergone mutations, resulting in new virus variants. While no treatment is currently available, a naturally derived molecule with known antiviral properties could be used as a potential treatment. Bromelain is an enzyme found in the fruit and stem of pineapples. This substance has been shown to have a broad antiviral activity. In this article, we analyse the ability of bromelain to counteract various variants of the SARS-CoV-2 by targeting bromelain binding on the side of this viral interaction with human angiotensin-converting enzyme 2 (hACE2) using molecular docking and molecular dynamics simulation approaches. We have succeeded in making three-dimensional configurations of various RBD variants using protein modelling. Bromelain exhibited good binding affinity toward various variants of RBDs and binds right at the binding site between RBDs and hACE2. This result is also presented in the modelling between Bromelain, RBD, and hACE2. The molecular dynamics (MD) simulations study revealed significant stability of the bromelain and RBD proteins separately up to 100 ns with an RMSD value of 2 Å. Furthermore, despite increases in RMSD and changes in Rog values of complexes, which are likely due to some destabilized interactions between bromelain and RBD proteins, two proteins in each complex remained bonded, and the site where the two proteins bind remained unchanged. This finding indicated that bromelain could have an inhibitory effect on different SARS-CoV-2 variants, paving the way for a new SARS-CoV-2 inhibitor drug. However, more in vitro and in vivo research on this potential mechanism of action is required.

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Virtual Screening of Acetylcholinesterase Inhibitors Using the Lipinski’s Rule of Five and ZINC Databank

BioMed Research International ◽

10.1155/2015/870389 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 22

Author(s):

Pablo Andrei Nogara ◽

Rogério de Aquino Saraiva ◽

Diones Caeran Bueno ◽

Lílian Juliana Lissner ◽

Cristiane Lenz Dalla Corte ◽

...

Keyword(s):

Molecular Docking ◽

Virtual Screening ◽

Ache Activity ◽

Acetylcholinesterase Inhibitors ◽

Behavioral Changes ◽

Lipinski’S Rule ◽

Memory Impairments ◽

Compound C ◽

Lipinski’S Rule Of Five

Alzheimer’s disease (AD) is a progressive and neurodegenerative pathology that can affect people over 65 years of age. It causes several complications, such as behavioral changes, language deficits, depression, and memory impairments. One of the methods used to treat AD is the increase of acetylcholine (ACh) in the brain by using acetylcholinesterase inhibitors (AChEIs). In this study, we used the ZINC databank and the Lipinski’s rule of five to perform a virtual screening and a molecular docking (using Auto Dock Vina 1.1.1) aiming to select possible compounds that have quaternary ammonium atom able to inhibit acetylcholinesterase (AChE) activity. The molecules were obtained by screening and furtherin vitroassays were performed to analyze the most potent inhibitors through the IC50value and also to describe the interaction models between inhibitors and enzyme by molecular docking. The results showed that compound D inhibited AChE activity from different vertebrate sources and butyrylcholinesterase (BChE) fromEquus ferus(EfBChE), with IC50ranging from 1.69 ± 0.46 to 5.64 ± 2.47 µM. Compound D interacted with the peripheral anionic subsite in both enzymes, blocking substrate entrance to the active site. In contrast, compound C had higher specificity as inhibitor ofEfBChE. In conclusion, the screening was effective in finding inhibitors of AChE and BuChE from different organisms.

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Screening nucleotide and nucleoside analogues as potential inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase by the molecular docking method for the treatment of COVID-19

Ministry of Science and Technology, Vietnam ◽

10.31276/vjst.63(9).14-21 ◽

2021 ◽

Vol 63 (9) ◽

pp. 14-21

Author(s):

Thi Thu Hang Ta ◽

◽

Bao Kim Nguyen ◽

Dang Huy Le ◽

Thanh Tung Bui ◽

...

Keyword(s):

Molecular Docking ◽

Rna Polymerase ◽

Health Concern ◽

Pharmacokinetic Parameters ◽

Rna Dependent Rna Polymerase ◽

Lipinski’S Rule ◽

Docking Method ◽

Lipinski’S Rule Of Five

The COVID-19 pandemic triggering acute respiratory syndrome is a major global health concern. The SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) enzyme regulating viral replication has been evaluated as a potential therapeutic target for inhibition of the infection of SARS-CoV-2. In this study, we evaluated the ability of RNA-dependent RNA polymerase drug inhibitors by using molecular docking in silico model. Lipinski’s rule of Five was used to evaluate drug - like properties of potential compound. Pharmacokinetic parameters of potential compounds were assessed using the pkCSM tool. Based on previous publications, we have collected 100 compounds. The results exhibited that 18 compounds have RdRp inhibitory activity stronger than the remdesivir as reference compounds. The Lipinski’s rule of Five showed that 17 among 18 compounds had proprietary drug-likenesss. Compounds including novuridine, didanosine, sofosbuvir, puromycin, defibrotite, gemcitabine, and nikkomycins are the most negative energies and have pharmacokinetic good absorption, not metabolised in the liver, excreted by the kidney and may have hepatotoxicity properties. Therefore, it is necessary to conduct the in vitro and in vivo assays to developthese compounds into drugs for COVID-19 treatment

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Molecular Docking Studies of Flavonoids from Andrographis paniculata as Potential Acetylcholinesterase, Butyrylcholinesterase and Monoamine Oxidase Inhibitors Towards the Treatment of Neurodegenerative Diseases

Biointerface Research in Applied Chemistry ◽

10.33263/briac113.98719879 ◽

2020 ◽

Vol 11 (3) ◽

pp. 9871-9879

Keyword(s):

Molecular Docking ◽

Monoamine Oxidase ◽

Neurodegenerative Diseases ◽

Docking Studies ◽

Monoamine Oxidase Inhibitors ◽

Andrographis Paniculata ◽

Lipinski’S Rule ◽

Bioinformatic Tools ◽

Pubchem Database ◽

Lipinski’S Rule Of Five

Neurodegenerative diseases have been characterized by loss of neuron structures as well as their functions. This study was designed to assess molecular docking of flavonoids from Andrographis paniculata as potential acetylcholinesterase, butyrylcholinesterase, and monoamine oxidase inhibitors in the treatment of neurodegenerative diseases. Eight identified possible inhibitors of acetylcholinesterase, butyrylcholinesterase, and monoamine oxidase from Andrographis paniculata were retrieved from the PubChem database. The molecular docking, ADMET, and Lipinski’s rule of five were examined using different bioinformatic tools. It was shown that only rutin has the highest binding affinity (-12.6 kcal/mol) than the standard used. ADMET results demonstrated that all the eight compounds are druggable candidates except rutin. Also, only tangeritin has a blood-brain barrier (BBB) permeation potential. Hence, it can be deduced that all flavonoid compounds from Andrographis paniculata are orally druggable, which can make them useful in the treatment of neurodegenerative diseases better than donepezil.

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Study of Baicalin toward COVID-19 Treatment: In silico Target Analysis and in vitro Inhibitory Effects on SARS-CoV-2 Proteases

Biomedicine Hub ◽

10.1159/000519564 ◽

2021 ◽

pp. 122-137

Author(s):

Chingju Lin ◽

Fuu-Jen Tsai ◽

Yuan-Man Hsu ◽

Tsung-Jung Ho ◽

Guo-Kai Wang ◽

...

Keyword(s):

Molecular Docking ◽

Binding Affinity ◽

Pathway Analysis ◽

Acute Inflammation ◽

Inhibitory Effect ◽

Pharmacological Effects ◽

Inhibitory Effects ◽

Rna Dependent Rna Polymerase ◽

Negative Impacts

Negative impacts of COVID-19 on human health and economic and social activities urge scientists to develop effective treatments. Baicalin is a natural flavonoid, extracted from a traditional medicinal plant, previously reported with anti-inflammatory activity. In this study, we used pharmacophore fitting and molecular docking to screen and determine docking patterns and the binding affinity of baicalin on 3 major targets of SARS-CoV-2 (3-chymotrypsin-like cysteine protease [3CLpro], papain-like protease [PLpro], and RNA-dependent RNA polymerase). The obtained data revealed that baicalin has high pharmacophore fitting on 3CLpro and predicted good binding affinity on PLpro. Moreover, using the enzymatic assay, we examined the inhibitory effect of baicalin in vitro on the screened enzymes. Baicalin also exhibits inhibitory effect on these proteases in vitro. Additionally, we performed pharmacophore-based screening of baicalin on human targets and conducted pathway analysis to explore the potential cytoprotective effects of baicalin in the host cell that may be beneficial for COVID-19 treatment. The result suggested that baicalin has multiple targets in human cell that may induce multiple pharmacological effects. The result of pathway analysis implied that these targets may be associated with baicalin-induced bioactivities that are involved with signals of pro-inflammation factors, such as cytokine and chemokine. Taken together with supportive data from the literature, the bioactivities of bailalin may be beneficial for COVID-19 treatment by reducing cytokine-induced acute inflammation. In conclusion, baicalin is potentially a good candidate for developing new therapeutic to treat COVID-19.

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Design, synthesis, characterization, in vitro screening, molecular docking, 3D-QSAR, and ADME-Tox investigations of novel pyrazole derivatives as antimicrobial agents

New Journal of Chemistry ◽

10.1039/d1nj05621b ◽

2022 ◽

Author(s):

Mohammed CHALKHA ◽

Mohamed Akhazzane ◽

Fatima Zahrae Moussaid ◽

Ossama Daoui ◽

Asmae Nakkabi ◽

...

Keyword(s):

Molecular Docking ◽

Antimicrobial Agents ◽

3D Qsar ◽

Spectroscopic Techniques ◽

In Vitro Screening ◽

Pyrazole Derivatives ◽

Design Synthesis ◽

Practical Procedure

In this work, we report the synthesis of some new pyrazole derivatives via an efficient and practical procedure. The structures of the obtained compounds were established using different spectroscopic techniques...

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Synthesis and In Vitro Screening of Novel Heterocyclic β-d-Gluco- and β-d-Galactoconjugates as Butyrylcholinesterase Inhibitors

Molecules ◽

10.3390/molecules24152833 ◽

2019 ◽

Vol 24 (15) ◽

pp. 2833

Author(s):

Krešimir Baumann ◽

Lorena Kordić ◽

Marko Močibob ◽

Goran Šinko ◽

Srđanka Tomić

Keyword(s):

Active Site ◽

Kinetic Studies ◽

Inhibitory Effect ◽

In Vitro Screening ◽

Sugar Moiety ◽

Brain Barrier Permeability ◽

The Central Nervous System ◽

Key Residues ◽

Micromolar Range

The development of selective butyrylcholinesterase (BChE) inhibitors may improve the treatment of Alzheimer’s disease by increasing lower synaptic levels of the neurotransmitter acetylcholine, which is hydrolysed by acetylcholinesterase, as well as by overexpressed BChE. An increase in the synaptic levels of acetylcholine leads to normal cholinergic neurotransmission and improved cognitive functions. A series of 14 novel heterocyclic β-d-gluco- and β-d-galactoconjugates were designed and screened for inhibitory activity against BChE. In the kinetic studies, 4 out of 14 compounds showed an inhibitory effect towards BChE, with benzimidazolium and 1-benzylbenzimidazolium substituted β-d-gluco- and β-d-galacto-derivatives in a 10–50 micromolar range. The analysis performed by molecular modelling indicated key residues of the BChE active site, which contributed to a higher affinity toward the selected compounds. Sugar moiety in the inhibitor should enable better blood–brain barrier permeability, and thus increase bioavailability in the central nervous system of these compounds.

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Thiourea Derivatives Based on the Dapsone‐Naphthoquinone Hybrid as Anticancer and Antimicrobial Agents: In Vitro Screening and Molecular Docking Studies

ChemistrySelect ◽

10.1002/slct.201903179 ◽

2020 ◽

Vol 5 (2) ◽

pp. 847-852 ◽

Cited By ~ 2

Author(s):

Aazam Alimohammadi ◽

Hossein Mostafavi ◽

Majid Mahdavi

Keyword(s):

Molecular Docking ◽

Antimicrobial Agents ◽

Docking Studies ◽

In Vitro Screening ◽

Thiourea Derivatives ◽

Molecular Docking Studies

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Assessment of Immunogenicity and Neutralisation Efficacy of Viral-Vectored Vaccines Against Chikungunya Virus

Viruses ◽

10.3390/v11040322 ◽

2019 ◽

Vol 11 (4) ◽

pp. 322 ◽

Cited By ~ 10

Author(s):

César López-Camacho ◽

Young Chan Kim ◽

Joshua Blight ◽

Marcos Lazaro Moreli ◽

Eduardo Montoya-Diaz ◽

...

Keyword(s):

Chikungunya Virus ◽

Pacific Islands ◽

High Capacity ◽

Febrile Illness ◽

Structural Proteins ◽

Vaccine Platform ◽

Cell Responses ◽

Efficacious Vaccine

Chikungunya virus (CHIKV) has caused extensive outbreaks in several countries within the Americas, Asia, Oceanic/Pacific Islands, and Europe. In humans, CHIKV infections cause a debilitating disease with acute febrile illness and long-term polyarthralgia. Acute and chronic symptoms impose a major economic burden to health systems and contribute to poverty in affected countries. An efficacious vaccine would be an important step towards decreasing the disease burden caused by CHIKV infection. Despite no licensed vaccine is yet available for CHIKV, there is strong evidence of effective asymptomatic viral clearance due to neutralising antibodies against the viral structural proteins. We have designed viral-vectored vaccines to express the structural proteins of CHIKV, using the replication-deficient chimpanzee adenoviral platform, ChAdOx1. Expression of the CHIKV antigens results in the formation of chikungunya virus-like particles. Our vaccines induce high frequencies of anti-chikungunya specific T-cell responses as well as high titres of anti-CHIKV E2 antibodies with high capacity for in vitro neutralisation. Our results indicate the potential for further clinical development of the ChAdOx1 vaccine platform in CHIKV vaccinology.

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