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

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.

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Targeting Virus-Host Interaction: An in Silico Approach to Develop Promising Inhibitors Against COVID-19

10.26434/chemrxiv.12198369 ◽

2020 ◽

Author(s):

Jitendra Subhash Rane ◽

Aroni Chatterjee ◽

Rajni Khan ◽

Abhijeet Kumar ◽

Shashikant Ray

Keyword(s):

Angiotensin Converting Enzyme ◽

In Silico ◽

Virus Disease ◽

Spike Protein ◽

Converting Enzyme ◽

Host Cell Membrane ◽

Angiotensin Converting Enzyme 2 ◽

Host Interaction

The entire human population all over the globe is currently facing appalling conditions due to the spread of infection from COVID-19 (corona virus disease-2019). In the last few months enormous amount of studies have been continuously trying to target several potential drug sites to identify a novel therapeutic target. Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is also being targeted by several scientific groups as a novel drug target. The spike glycoprotein protein is present on the surface of the virion and binds to the human angiotensin-converting enzyme-2 (hACE2) membrane receptor thereby promoting its fusion to the host cell membrane. The binding and internalization of the virus is a crucial step in the process of infection and hence any molecule that can inhibit this, certainly holds a significant therapeutic value. We have identified AP-NP (2-(2-amino-5-(naphthalen-2- yl)pyrimidin-4-yl)phenol) and AP-4-Me-Ph (2-(2-amino-5-(p-tolyl)pyrimidin-4-yl)phenol) from a group of diaryl pyrimidine derivatives which appear to bind at the interface of hACE2-SARS-CoV-2S complex (human angiotensin converting enzyme 2 and spike glycoprotein complex) with a low binding energy (<-8 Kcal/mol). In this in-silico study we also found that AP-NP interacts with S1 domain of C-terminal part of SARS-CoV-2S however AP-4-Me-Ph was found to interact with S2 domain of SARS-CoV-2S. The result suggested that AP-NP and AP-4-Me-Ph have potential to inhibit the interaction between spike protein and hACE2 receptor also AP-4-Me-Ph might be prevent internalization of the virion within the host. Further in vitro and in vivo study will strengthen these drug candidates against the COVID-19.

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Targeting Virus-Host Interaction: An in Silico Approach to Develop Promising Inhibitors Against COVID-19

10.26434/chemrxiv.12198369.v1 ◽

2020 ◽

Author(s):

Jitendra Subhash Rane ◽

Aroni Chatterjee ◽

Rajni Khan ◽

Abhijeet Kumar ◽

Shashikant Ray

Keyword(s):

Angiotensin Converting Enzyme ◽

In Silico ◽

Virus Disease ◽

Spike Protein ◽

Converting Enzyme ◽

Host Cell Membrane ◽

Angiotensin Converting Enzyme 2 ◽

Host Interaction

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In silico and in vitro Demonstration of Homoharrintonine Antagonism of RBD-ACE2 Binding and its Anti-inflammatory and anti-thrombogenic Properties in a 3D human vascular lung model

10.1101/2021.05.02.442384 ◽

2021 ◽

Author(s):

Shalini Saxena ◽

Kranti Meher ◽

Madhuri Rotella ◽

Subhramanyam Vangala ◽

Satish Chandran ◽

...

Keyword(s):

Molecular Docking ◽

Active Sites ◽

Cell Model ◽

Antiviral Drugs ◽

Lung Model ◽

Host Cells ◽

Spike Protein ◽

Prevention And Treatment ◽

Anti Inflammatory

Since 2019 the world has seen severe onslaught of SARS-CoV-2 viral pandemic. There is an urgent need for drugs that can be used to either prevent or treat the potentially fatal disease COVD-19. To this end, we screened FDA approved antiviral drugs which could be repurposed for COVID-19 through molecular docking approach in the various active sites of receptor binding domain (RBD). The RBD domain of SARS-CoV-2 spike protein is a promising drug target due to its pivotal role in viral-host attachment. Specifically, we focussed on identifying antiviral drugs which could a) block the entry of virus into host cells, b) demonstrate anti-inflammatory and/or anti-thrombogenic properties. Drugs which poses both properties could be useful for prevention and treatment of the disease. While we prioritized a few antiviral drugs based on molecular docking, corroboration with in vitro studies including a new 3D human vascular lung model strongly supported the potential of Homoharringtonine, a drug approved for chronic myeloid leukaemia to be repurposed for COVID-19. This natural product drug not only antagonized the biding of SARS-CoV-2 spike protein RBD binding to human angiotensin receptor 2 (ACE-2) protein but also demonstrated for the first time anti-thrombogenic and anti-leukocyte adhesive properties in a human cell model system. Overall, this work provides an important lead for development of rapid treatment of COVID-19 and also establishes a screening paradigm using molecular modelling and 3D human vascular lung model of disease to identify drugs with multiple desirable properties for prevention and treatment of COVID-19.

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Molecular Docking and Preclinical Study of Five-MemberedS,S-Palladaheterocycle as Hepatoprotective Agent

Advanced Pharmaceutical Bulletin ◽

10.15171/apb.2019.079 ◽

2019 ◽

Vol 9 (4) ◽

pp. 674-684 ◽

Cited By ~ 1

Author(s):

Nail Salavatovich Akhmadiev ◽

Albina Midkhatovna Galimova ◽

Vnira Rakhimovna Akhmetova ◽

Veronika Radievna Khairullina ◽

Rozaliia Akramovna Galimova ◽

...

Keyword(s):

Molecular Docking ◽

Survival Data ◽

Active Sites ◽

Cytochromes P450 ◽

Hepatoprotective Activity ◽

Preclinical Study ◽

Therapeutic Effects ◽

Preclinical Trials

Purpose: In order to investigate mechanisms underlying the hepatoprotective action of S,Spalladaheterocycle,inhibition of cytochromes P450 has been modeled by molecular dockingof four palladaheterocycle stereoisomers to the active sites of an enzymatic oxidase system. Toobtain a deeper insight into biochemical aspects providing a basis for the therapeutic effects offive-membered palladacycles (as mixture of stereoisomers), a number of preclinical trials hasbeen conductedMethods: 2D and 3D structures of palladaheterocycle stereoisomers were obtained viaconverting into SDF files by means of software MarvinSketch. Binding of palladaheterocycle atthe active sites of cytochromes P450 2E1 and P450 2C9 has been studied by molecular dockingusing LeadIT 2.3.2. Hepatoprotective activity of palladaheterocycle at 2.5, 25 and 250 mg/kgdoses has been studied based on a model of acute intoxication by CCl4 using in vivo methods.Results: By molecular docking it was identify amino acid fragments responsible for bindingwith palladacyclic isomers. The tested compound is comparable, in terms of its activity tothe hepatoprotective drug SAM according to the in vivo and in vitro experiments such asanimal survival data, the efficiency of correction of the cytolytic syndrome, the liver excretoryfunction, carbohydrate, protein and lipid metabolism, and the correction efficiency of the liverantitoxic function (the latter has been determined based on the results of a hexobarbital controlexperiment).Conclusion: Taking into account results obtained in vivo, in vitro and in silico, it can be concludedthat the five-membered S,S-palladaheterocycle effectively protect the liver against acute damagecaused by CCl4, via activation of catalase and glucuronyltransferase, as well as via inhibition ofthe oxidative stress enzymes.

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In-vivo Protection from SARS-CoV-2 infection by ATN-161 in k18-hACE2 transgenic mice

10.1101/2021.05.08.443275 ◽

2021 ◽

Author(s):

Amruta Narayanappa ◽

Elizabeth B Engler-Chiurazzi ◽

Isabel C Murray-Brown ◽

Timothy E Gressett ◽

Ifechukwude J Biose ◽

...

Keyword(s):

Protein Interactions ◽

Viral Entry ◽

Therapeutic Potential ◽

Host Cells ◽

Spike Protein ◽

Cell Infection ◽

Integrin Alpha5beta1 ◽

Chemokine Ligand

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an infectious disease that has spread worldwide. Current treatments are limited in both availability and efficacy, such that improving our understanding of the factors that facilitate infection is urgently needed to more effectively treat infected individuals and to curb the pandemic. We and others have previously demonstrated the significance of interactions between the SARS-CoV-2 spike protein, integrin alpha5beta1 and human ACE2 to facilitate viral entry into host cells in vitro. We previously found that inhibition of integrin alpha5beta1 by the clinically validated small peptide ATN-161 inhibits these spike protein interactions and cell infection in vitro. In continuation with our previous findings, here we have further evaluated the therapeutic potential of ATN-161 on SARS-CoV-2 infection in k18-hACE2 transgenic (SARS-CoV-2 susceptible) mice in vivo. We discovered that treatment with single- or repeated intravenous doses of ATN-161 (1 mg/kg) within 48 hours after intranasal inoculation with SARS-CoV-2 lead to a reduction of lung viral load, viral immunofluorescence and improved lung histology in a majority of mice 72 hours post-infection. Furthermore, ATN-161 reduced SARS-CoV-2-induced increased expression of lung integrin alpha 5 and alpha v (an alpha 5-related integrin that has also been implicated in SARS-CoV-2 interactions) as well as the C-X-C motif chemokine ligand 10 (Cxcl10), further supporting the potential involvement of these integrins, and the anti-inflammatory potential of ATN-161, respectively, in SARS-CoV-2 infection. To the best of our knowledge, this is the first study demonstrating the potential therapeutic efficacy of targeting integrin alpha5beta1 in SARS-CoV-2 infection in vivo and supports the development of ATN-161 as a novel SARS-CoV-2 therapy.

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Conformational Perturbation of SARS-CoV-2 Spike Protein Using N-Acetyl Cysteine, a Molecular Scissor: A Probable Strategy to Combat COVID-19

10.26434/chemrxiv.12687923.v1 ◽

2020 ◽

Author(s):

Utsab Debnath ◽

Varun Dewaker ◽

Yenamandra S. Prabhakar ◽

Parthasarathi Bhattacharyya ◽

Amit Mandal

Keyword(s):

Disulfide Bond ◽

In Silico ◽

Ex Vivo ◽

Virus Disease ◽

Spike Protein ◽

Early 21St Century ◽

Acetyl Cysteine ◽

Structural Architecture

The infection caused by Severe Acute Respiratory Syndrome–CoronaVirus-2 (SARS-CoV-2) resulted in a pandemic across the globe with a huge death toll. The symptoms from SARS-CoV2 appear somewhat similar to the SARS-CoV-1 infection that appeared in early 21st century but the infectivity is far higher for the SARS-CoV-2. The virus attaches itself to exposed human epithelial cells through the spike protein. Recently discovered crystal structure of the complex of spike protein of SARS-CoV-2 with human angiotensin-converting enzyme 2 (ACE2) receptor indicated that the virus binds with the host cell very strongly. We hypothesized that the perturbation of the functionally active conformation of spike protein through the reduction of a solvent accessible disulfide bond (Cys391-Cys525) that provides its structural architecture, may 2 be a feasible strategy to disintegrate the spike protein from ACE2 receptor and thereby prevent the infection. Using in silico platform we showed that N-acetyl cysteine (NAC), a drug used as antioxidant and mucolytic agent, binds in the close proximity of above disulfide bond. The reduction of the disulfide bond via thiol/disulfide exchange, followed by covalent conjugation of NAC perturbed the stereo specific orientations of interacting key residues of spike protein. This resulted in threefold weakening in the binding affinity of spike protein with ACE2 receptor. This opens avenues for exploring the effect of NAC in vitro, ex vivo and in vivo and on successful observation of the similar effect as in silico, the intervention of NAC may be translated in the pharmacoprevention and treatment of Corona virus disease 2019.

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Virtual Screening of Phytochemicals by Targeting HR1 Domain of SARS-CoV-2 S Protein: Molecular Docking, Molecular Dynamics Simulations, and DFT Studies

BioMed Research International ◽

10.1155/2021/6661191 ◽

2021 ◽

Vol 2021 ◽

pp. 1-19

Author(s):

Arshia Majeed ◽

Waqar Hussain ◽

Farkhanda Yasmin ◽

Ammara Akhtar ◽

Nouman Rasool

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Molecular Dynamics Simulations ◽

Density Functional ◽

Spike Protein ◽

Effective Vaccine ◽

High Morbidity ◽

Dynamics Simulations

The recent COVID-19 pandemic has impacted nearly the whole world due to its high morbidity and mortality rate. Thus, scientists around the globe are working to find potent drugs and designing an effective vaccine against COVID-19. Phytochemicals from medicinal plants are known to have a long history for the treatment of various pathogens and infections; thus, keeping this in mind, this study was performed to explore the potential of different phytochemicals as candidate inhibitors of the HR1 domain in SARS-CoV-2 spike protein by using computer-aided drug discovery methods. Initially, the pharmacological assessment was performed to study the drug-likeness properties of the phytochemicals for their safe human administration. Suitable compounds were subjected to molecular docking to screen strongly binding phytochemicals with HR1 while the stability of ligand binding was analyzed using molecular dynamics simulations. Quantum computation-based density functional theory (DFT) analysis was constituted to analyze the reactivity of these compounds with the receptor. Through analysis, 108 phytochemicals passed the pharmacological assessment and upon docking of these 108 phytochemicals, 36 were screened passing a threshold of -8.5 kcal/mol. After analyzing stability and reactivity, 5 phytochemicals, i.e., SilybinC, Isopomiferin, Lycopene, SilydianinB, and Silydianin are identified as novel and potent candidates for the inhibition of HR1 domain in SARS-CoV-2 spike protein. Based on these results, it is concluded that these compounds can play an important role in the design and development of a drug against COVID-19, after an exhaustive in vitro and in vivo examination of these compounds, in future.

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Effects of Nervilia fordii Extract on Pulmonary Fibrosis Through TGF-β/Smad Signaling Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.659627 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yufeng Yao ◽

Yue Yuan ◽

Zenghui Lu ◽

Yunxia Ma ◽

Yuanyuan Xie ◽

...

Keyword(s):

Molecular Docking ◽

Pulmonary Fibrosis ◽

Signaling Pathway ◽

Therapeutic Effects ◽

Collagen Deposition ◽

Smad Signaling ◽

Smad Signaling Pathway ◽

Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial pulmonary disease with a poor prognosis. The extract of Nervilia fordii (NFE) has shown remarkable benefit in the treatment of acute lung injury, lung cancer, and severe acute respiratory syndrome (SARS). However, the potential mechanism and efficacy of NFE in the treatment of IPF remain unknown. In this study, a systematic network pharmacology analysis was used to predict the mechanism and efficacy of NFE in the treatment of IPF, based on the major components of NFE elucidated by UPLC-TOF-MS/MS. The potential molecular interactions between the compounds and potential targets were predicted using molecular docking. In vivo, rats with pulmonary fibrosis induced by a single intratracheal injection of bleomycin (BLM) were orally administered NFE for 14 days. Lung index and biochemical levels were determined, and histopathological analysis using hematoxylin and eosin (H&E) and Masson staining was performed. The effects of NFE on fibroblast proliferation in Lipopolysaccharide (LPS) and TGF-β1-induced mouse 3T6 fibroblasts were evaluated in vitro. In total, 20 components were identified in NFE, and 102 potential targets for IPF treatment were predicted. These targets potentially participate in processes regulated by transmembrane receptor protein tyrosine kinase, ERBB2, and et al. Molecular docking results predicted high affinity interactions between three components (rhamnazin, rhamnetin, and rhamnocitrin) and the potential targets, suggesting that TGF-β is the most important potential target of NFE in the treatment of pulmonary fibrosis. NFE significantly decreased the lung index and alleviated BLM-induced pulmonary fibrosis in rats. Histopathological observation of lung tissues showed that NFE alleviated inflammation and collagen deposition in BLM-induced rats. NFE inhibited the migration of LPS- and TGF-β1-induced 3T6 fibroblasts, reduced the contents of hydroxyproline and collagen, and contributed to anti-inflammation and anti-oxidation. With the intervention of NFE, the protein and RNA expression of TGF-β1, a-SMA, Smad3/4, p-Smad3/4, CTGF, and p-ERK1/2 were significantly downregulated, while Smad7 and ERK1/2 were upregulated significantly in vivo and in vitro. These findings indicated that NFE may exert therapeutic effects on pulmonary fibrosis by alleviating inflammation, oxidation, and collagen deposition. The mechanism related to the inhibition of the TGF-β/Smad signaling pathway.

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Virtual Screening of Natural Products against Type II Transmembrane Serine Protease (TMPRSS2), the Priming Agent of Coronavirus 2 (SARS-CoV-2)

Molecules ◽

10.3390/molecules25102271 ◽

2020 ◽

Vol 25 (10) ◽

pp. 2271 ◽

Cited By ~ 21

Author(s):

Noor Rahman ◽

Zarrin Basharat ◽

Muhammad Yousuf ◽

Giuseppe Castaldo ◽

Luca Rastrelli ◽

...

Keyword(s):

Molecular Docking ◽

Three Dimensional ◽

Natural Compounds ◽

Structural Features ◽

Host Cells ◽

Dimensional Structure ◽

Active Site Residues ◽

Transmembrane Serine Protease

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused about 2 million infections and is responsible for more than 100,000 deaths worldwide. To date, there is no specific drug registered to combat the disease it causes, named coronavirus disease 2019 (COVID-19). In the current study, we used an in silico approach to screen natural compounds to find potent inhibitors of the host enzyme transmembrane protease serine 2 (TMPRSS2). This enzyme facilitates viral particle entry into host cells, and its inhibition blocks virus fusion with angiotensin-converting enzyme 2 (ACE2). This, in turn, restricts SARS-CoV-2 pathogenesis. A three-dimensional structure of TMPRSS2 was built using SWISS-MODEL and validated by RAMPAGE. The natural compounds library Natural Product Activity and Species Source (NPASS), containing 30,927 compounds, was screened against the target protein. Two techniques were used in the Molecular Operating Environment (MOE) for this purpose, i.e., a ligand-based pharmacophore approach and a molecular docking-based screening. In total, 2140 compounds with pharmacophoric features were retained using the first approach. Using the second approach, 85 compounds with molecular docking comparable to or greater than that of the standard inhibitor (camostat mesylate) were identified. The top 12 compounds with the most favorable structural features were studied for physicochemical and ADMET (absorption, distribution, metabolism, excretion, toxicity) properties. The low-molecular-weight compound NPC306344 showed significant interaction with the active site residues of TMPRSS2, with a binding energy score of −14.69. Further in vitro and in vivo validation is needed to study and develop an anti-COVID-19 drug based on the structures of the most promising compounds identified in this study.

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Discovery of Potential Antiviral Compounds against Hendra Virus by Targeting Its Receptor-Binding Protein (G) Using Computational Approaches

Molecules ◽

10.3390/molecules27020554 ◽

2022 ◽

Vol 27 (2) ◽

pp. 554

Author(s):

Faisal Ahmad ◽

Aqel Albutti ◽

Muhammad Hamza Tariq ◽

Ghufranud Din ◽

Muhammad Tahir ul Qamar ◽

...

Keyword(s):

Molecular Docking ◽

Surface Area ◽

Active Sites ◽

Research Work ◽

Primary Objective ◽

Hendra Virus ◽

Host Cells ◽

Antiviral Compounds

Hendra virus (HeV) belongs to the paramyxoviridae family of viruses which is associated with the respiratory distress, neurological illness, and potential fatality of the affected individuals. So far, no competitive approved therapeutic substance is available for HeV. For that reason, the current research work was conducted to propose some novel compounds, by adopting a Computer Aided Drug Discovery approach, which could be used to combat HeV. The G attachment Glycoprotein (Ggp) of HeV was selected to achieve the primary objective of this study, as this protein makes the entry of HeV possible in the host cells. Briefly, a library of 6000 antiviral compounds was screened for potential drug-like properties, followed by the molecular docking of short-listed compounds with the Protein Data Bank (PDB) structure of Ggp. Docked complexes of top two hits, having maximum binding affinities with the active sites of Ggp, were further considered for molecular dynamic simulations of 200 ns to elucidate the results of molecular docking analysis. MD simulations and Molecular Mechanics Energies combined with the Generalized Born and Surface Area (MMGBSA) or Poisson–Boltzmann and Surface Area (MMPBSA) revealed that both docked complexes are stable in nature. Furthermore, the same methodology was used between lead compounds and HeV Ggp in complex with its functional receptor in human, Ephrin-B2. Surprisingly, no major differences were found in the results, which demonstrates that our identified compounds can also perform their action even when the Ggp is attached to the Ephrin-B2 ligand. Therefore, in light of all of these results, we strongly suggest that compounds (S)-5-(benzylcarbamoyl)-1-(2-(4-methyl-2-phenylpiperazin-1-yl)-2-oxoethyl)-6-oxo-3,6-dihydropyridin-1-ium-3-ide and 5-(cyclohexylcarbamoyl)-1-(2-((2-(3-fluorophenyl)-2-methylpropyl)amino)-2-oxoethyl)-6-oxo-3,6-dihydropyridin-1-ium-3-ide could be considered as potential therapeutic agents against HeV; however, further in vitro and in vivo experiments are required to validate this study.

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