Membrane-Mediated Sars-cov-2 Host Cell Entry: Potential Inhibitory Roles of Terpenoids in Silico

Abstract Targeting viral cell entry proteins is an emerging therapeutic strategy for inhibiting the first stage of SARS-CoV-2 infection. In this study, 106 bioactive terpenoids from African medicinal plants were screened through molecular docking analysis against human angiotensin-converting enzyme 2 (hACE2), human transmembrane protease serine 2 (TMPRSS2) and the S proteins of SARS-CoV-2, SARS-CoV and MERS-CoV. In silico ADMET and drug-likeness prediction, molecular dynamics simulation (MDS), binding free energy calculations and clustering analysis of MDS trajectories were performed on the top docked compounds to respective targets. The results revealed eight terpenoids with high binding tendencies to the catalytic residues of different targets. Pentacyclic terpenoids: 24-methylene cycloartenol and isoiguesterin interacted with the hACE2 binding hotspots for the SARS-CoV-2 Spike protein. 11-hydroxy-2 - (3,4-dihydroxybenzoyloxy) abieta -5,7,9 (11),13-tetraene-12-one, 11-hydroxy-2 -(4-hydroxybenzoyloxy)-abieta- 5,7,9(11),13-tetraene-12-one and other abietane diterpenes interacted strongly with the S1-specificy pocket of TMPRSS2. 3-benzoylhosloppone and cucurbitacin interacted with the RBD and S2 subunit of SARS-CoV-2 spike protein respectively. The predicted druggable and ADMET favourable terpenoids formed structurally stable complexes in the simulated dynamics environment. These terpenoids provides core structure that can be exploited for further lead optimization to design drugs against SARS-CoV-2 cell mediated entry, subject to further in vitro and in vivo studies.

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Synthesis and studies of thiazolidinedione–isatin hybrids as α-glucosidase inhibitors for management of diabetes

Future Medicinal Chemistry ◽

10.4155/fmc-2020-0022 ◽

2021 ◽

Vol 13 (5) ◽

pp. 457-485

Author(s):

Ramandeep Kaur ◽

Rajnish Kumar ◽

Nilambra Dogra ◽

Ashok Kumar ◽

Ashok Kumar Yadav ◽

...

Keyword(s):

In Silico ◽

Binding Free Energy ◽

Biological Evaluation ◽

Free Energy Calculations ◽

Standard Drug ◽

Glucosidase Inhibitors ◽

Cytotoxicity Studies ◽

Cytotoxicity Assessment

Aim: Keeping in view the side effects associated with clinically used α-glucosidase inhibitors, novel thiazolidinedione–isatin hybrids were synthesized and evaluated by in vitro, in vivo and in silico procedures. Materials & methods: Biological evaluation, cytotoxicity assessment, molecular docking, binding free energy calculations and molecular dynamics studies were performed for hybrids. Results: The most potent inhibitor A-10 (IC50 = 24.73 ± 0.93 μM) was competitive in manner and observed as non-cytotoxic. A-10 possessed higher efficacy than the standard drug (acarbose) during in vivo biological testing. Conclusion: The enzyme inhibitory potential and safety profile of synthetic molecules was recognized after in vitro, in vivo, in silico and cytotoxicity studies. Further structural optimization of A-10 can offer potential hit molecules suitable for future investigations.

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SARS-CoV-2 host cell entry: an in silico investigation of potential inhibitory roles of terpenoids

Journal of Genetic Engineering and Biotechnology ◽

10.1186/s43141-021-00209-z ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Gideon A. Gyebi ◽

Oludare M. Ogunyemi ◽

Ibrahim M. Ibrahim ◽

Olalekan B. Ogunro ◽

Adegbenro P. Adegunloye ◽

...

Keyword(s):

Free Energy ◽

In Silico ◽

Md Simulation ◽

Binding Free Energy ◽

Free Energy Calculations ◽

Cell Entry ◽

Spike Protein ◽

Energy Calculations ◽

Wide Range ◽

Binding Free Energy Calculations

Abstract Background Targeting viral cell entry proteins is an emerging therapeutic strategy for inhibiting the first stage of SARS-CoV-2 infection. In this study, 106 bioactive terpenoids from African medicinal plants were screened through molecular docking analysis against human angiotensin-converting enzyme 2 (hACE2), human transmembrane protease serine 2 (TMPRSS2), and the spike (S) proteins of SARS-CoV-2, SARS-CoV, and MERS-CoV. In silico absorption-distribution-metabolism-excretion-toxicity (ADMET) and drug-likeness prediction, molecular dynamics (MD) simulation, binding free energy calculations, and clustering analysis of MD simulation trajectories were performed on the top docked terpenoids to respective protein targets. Results The results revealed eight terpenoids with high binding tendencies to the catalytic residues of different targets. Two pentacyclic terpenoids (24-methylene cycloartenol and isoiguesteri) interacted with the hACE2 binding hotspots for the SARS-CoV-2 spike protein, while the abietane diterpenes were found accommodated within the S1-specificity pocket, interacting strongly with the active site residues TMPRSS2. 3-benzoylhosloppone and cucurbitacin interacted with the RBD and S2 subunit of SARS-CoV-2 spike protein respectively. These interactions were preserved in a simulated dynamic environment, thereby, demonstrating high structural stability. The MM-GBSA binding free energy calculations corroborated the docking interactions. The top docked terpenoids showed favorable drug-likeness and ADMET properties over a wide range of molecular descriptors. Conclusion The identified terpenoids from this study provides core structure that can be exploited for further lead optimization to design drugs against SARS-CoV-2 cell-mediated entry proteins. They are therefore recommended for further in vitro and in vivo studies towards developing entry inhibitors against the ongoing COVID-19 pandemic.

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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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Andrographis paniculata (Burm. F.) Wall. Ex Nees, Andrographolide, and Andrographolide Analogues as SARS-CoV-2 Antivirals? A Rapid Review

Natural Product Communications ◽

10.1177/1934578x211016610 ◽

2021 ◽

Vol 16 (5) ◽

pp. 1934578X2110166

Author(s):

Xin Yi Lim ◽

Janice Sue Wen Chan ◽

Terence Yew Chin Tan ◽

Bee Ping Teh ◽

Mohd Ridzuan Mohd Abd Razak ◽

...

Keyword(s):

Inhibitory Activity ◽

In Silico ◽

Rna Binding ◽

Symptomatic Relief ◽

Andrographis Paniculata ◽

Spike Protein ◽

Rapid Review ◽

In Silico Studies

Drug repurposing is commonly employed in the search for potential therapeutic agents. Andrographis paniculata, a medicinal plant commonly used for symptomatic relief of the common cold, and its phytoconstituent andrographolide, have been repeatedly identified as potential antivirals against SARS-CoV-2. In light of new evidence emerging since the onset of the COVID-19 pandemic, this rapid review was conducted to identify and evaluate the current SARS-CoV-2 antiviral evidence for A. paniculata, andrographolide, and andrographolide analogs. A systematic search and screen strategy of electronic databases and gray literature was undertaken to identify relevant primary articles. One target-based in vitro study reported the 3CLpro inhibitory activity of andrographolide as being no better than disulfiram. Another Vero cell-based study reported potential SARS-CoV-2 inhibitory activity for both andrographolide and A. paniculata extract. Eleven in silico studies predicted the binding of andrographolide and its analogs to several key antiviral targets of SARS-CoV-2 including the spike protein-ACE-2 receptor complex, spike protein, ACE-2 receptor, RdRp, 3CLpro, PLpro, and N-protein RNA-binding domain. In conclusion, in silico and in vitro studies collectively suggest multi-pathway targeting SARS-CoV-2 antiviral properties of andrographolide and its analogs, but in vivo data are needed to support these predictions.

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High Throughput in Silico Identification of Novel Phytochemical Inhibitors for the Master Regulator of Inflammation (TNFα)

10.26434/chemrxiv.14178212.v2 ◽

2021 ◽

Author(s):

Pratap Kumar Parida ◽

Dipak Paul ◽

Debamitra Chakravorty

Keyword(s):

Small Molecule ◽

High Throughput ◽

In Silico ◽

Small Molecule Inhibitors ◽

Binding Free Energy ◽

Natural Compounds ◽

Free Energy Calculations ◽

Compound Libraries ◽

Relative Binding

<a>The over expression of Tumor necrosis factor-α (TNFα) has been implicated in a variety of disease and is classified as a therapeutic target for inflammatory diseases (Crohn disease, psoriasis, psoriatic arthritis, rheumatoid arthritis).Commercially available therapeutics are biologics which are associated with several risks and limitations. Small molecule inhibitors and natural compounds (saponins) were identified by researchers as lead molecules against TNFα, however, </a>they were often associated with high IC50 values which can lead to their failure in clinical trials. This warrants research related to identification of better small molecule inhibitors by screening of large compound libraries. Recent developments have demonstrated power of natural compounds as safe therapeutics, hence, in this work, we have identified TNFα phytochemical inhibitors using high throughput in silico screening approaches of 6000 phytochemicals followed by 200 ns molecular dynamics simulations and relative binding free energy calculations. The work yielded potent hits that bind to TNFα at its dimer interface. The mechanism targeted was inhibition of oligomerization of TNFα upon phytochemical binding to restrict its interaction with TNF-R1 receptor. MD simulation analysis resulted in identification of two phytochemicals that showed stable protein-ligand conformations over time. The two compounds were triterpenoids: Momordicilin and Nimbolin A with relative binding energy- calculated by MM/PBSA to be -190.5 kJ/Mol and -188.03 kJ/Mol respectively. Therefore, through this work it is being suggested that these phytochemicals can be used for further in vitro analysis to confirm their inhibitory action against TNFα or can be used as scaffolds to arrive at better drug candidates.

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Identification of Structurally Similar Phytochemicals to Quercetin with High SIRT1 Binding Affinity and Improving Diabetic Wound Healing by Using In silico Approaches

Biointerface Research in Applied Chemistry ◽

10.33263/briac126.76217632 ◽

2021 ◽

Vol 12 (6) ◽

pp. 7621-7632

Keyword(s):

Wound Healing ◽

In Silico ◽

Binding Free Energy ◽

Biological Properties ◽

In Vivo Studies ◽

Diabetic Wound ◽

Binding Modes ◽

Diabetic Wound Healing

Diabetes Mellitus is the most prevalent metabolic disorder that is increasing at an alarming rate worldwide. The unregulated glucose level leads to various types of health disorders, and one of the major diabetic complications is delayed wound healing. Due to the more side effects of synthetic drugs, there is a need to explore plants and their phytochemicals for medicinal purposes. It was found that Quercetin, a flavonoid, increases the rate of diabetic wound healing by enhancing the expression of SIRT1. This demands more insight towards Quercetin and its similar compounds, as it is hypothesized that similar compounds may have similar biological properties. Thus similarity searching was done to identify the most similar compounds of Quercetin, and then the molecular docking of the screened compounds was performed using AutoDock Vina. The unique ligands were docked into the active site of SIRT1 protein (PDB ID: 4ZZJ). The binding free energy of the interacting ligand with the protein was estimated. Six compounds were identified which possess the maximum structural similarity with Quercetin, and upon docking, it was found that gossypetin and herbacetin have similar binding modes and binding energy as that of Quercetin (-7.5 kcal/mol). Therefore, the hypothesis has been validated by in silico analysis. Our study identified two phytochemicals, Gossypetin, and Herbacetin which can prove beneficial for improving diabetic wound healing but needs to be validated further by in vitro and in vivo studies.

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In-silico Design, ADMET Screening, MM-GBSA Binding Free Energy of Some Novel Isoxazole Substituted 9-Anilinoacridines as HER2 Inhibitors Targeting Breast Cancer

Current Drug Research Reviews ◽

10.2174/2589977511666190912154817 ◽

2019 ◽

Vol 11 (2) ◽

pp. 118-128 ◽

Cited By ~ 6

Author(s):

Rajagopal Kalirajan ◽

Arumugasamy Pandiselvi ◽

Byran Gowramma ◽

Pandiyan Balachandran

Keyword(s):

Breast Cancer ◽

Free Energy ◽

In Silico ◽

Therapeutic Potential ◽

Binding Free Energy ◽

Breast Cancers ◽

Molecular Docking Study ◽

In Silico Admet

Background: Human Epidermal development factor Receptor-2 (HER2) is a membrane tyrosine kinase which is overexpressed and gene amplified in human breast cancers. HER2 amplification and overexpression have been linked to important tumor cell proliferation and survival pathways for 20% of instances of breast cancer. 9-aminoacridines are significant DNA-intercalating agents because of their antiproliferative properties. Objective: Some novel isoxazole substituted 9-anilinoacridines(1a-z) were designed by in-silico technique for their HER2 inhibitory activity. Docking investigations of compounds 1a-z are performed against HER2 (PDB id-3PP0) by using Schrodinger suit 2016-2. Methods: Molecular docking study for the designed molecules 1a-z are performed by Glide module, in-silico ADMET screening by QikProp module and binding free energy by Prime-MMGBSA module of Schrodinger suit. The binding affinity of designed molecules 1a-z towards HER2 was chosen based on GLIDE score. Results: Many compounds showed good hydrophobic communications and hydrogen bonding associations to hinder HER2. The compounds 1a-z, aside from 1z have significant Glide scores in the scope of - 4.91 to - 10.59 when compared with the standard Ethacridine (- 4.23) and Tamoxifen (- 3.78). The in-silico ADMET properties are inside the suggested about drug likeness. MM-GBSA binding of the most intense inhibitor is positive. Conclusion: The outcomes reveal that this study provides evidence for the consideration of isoxazole substituted 9-aminoacridine derivatives as potential HER2 inhibitors. The compounds, 1s,x,v,a,j,r with significant Glide scores may produce significant anti breast cancer activity and further in vitro and in vivo investigations may prove their therapeutic potential.

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Dual targeting of cytokine storm and viral replication in COVID-19 by plant-derived steroidal pregnanes in silico

10.21203/rs.3.rs-329239/v1 ◽

2021 ◽

Author(s):

Gideon A. Gyebi ◽

Oludare M. Ogunyemi ◽

Ibrahim M. Ibrahim ◽

Saheed O. Afolabi ◽

Joseph O. Adebayo

Keyword(s):

In Silico ◽

Glucocorticoid Receptors ◽

Active Regions ◽

Binding Energies ◽

Dynamics Simulation ◽

Mode Analysis ◽

High Morbidity ◽

Cytokine Storm

Abstract The high morbidity and mortality rate of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection arises majorly from the Acute Respiratory Distress Syndrome and “cytokine storm” syndrome, which is sustained by an aberrant systemic inflammatory response and elevated pro-inflammatory cytokines. Thus, phytocompounds with broad-spectrum anti-inflammatory activity that target multiple SARS-CoV-2 proteins will enhance the development of effective drugs against the disease. In this study, an in-house library of 106 steriodal plant-derived pregnanes (PDPs) was docked in the active regions of human glucocorticoid receptors (hGRs) in a comparative molecular docking analysis. Based on the minimal binding energy and a comparative dexamethason binding mode analysis, a list of top twenty ranked PDPs docked in the agonist conformation of hGR, with binding energies ranging between -9.8 and -11.2 Kcal/mol, was obtained and analyzed for interactions with the human Janus kinases 1 and Interleukins-6 and SARS-CoV-2 3-chymotrypsin-like protease, Papain-like protease and RNA-dependent RNA polymerase. For each target protein, the top three ranked PDPs were selected. Eight PDPs (bregenin, hirundigenin, anhydroholantogenin, atratogenin A, atratogenin B, glaucogenin A, glaucogenin C and glaucogenin D) with high binding tendencies to the catalytic residues of multiple targets were identified. A high degree of structural stability was observed from the 100 ns molecular dynamics simulation analyses of glaucogenin C and hirundigenin complexes of hGR. The selected top-eight ranked PDPs demonstrated favourable druggable and in silico ADMET properties. Thus, the therapeutic potentials of glaucogenin C and hirundigenin can be explored for further in vitro and in vivo studies.

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Vimentin binds to SARS-CoV-2 spike protein and antibodies targeting extracellular vimentin block in vitro uptake of SARS-CoV-2 virus-like particles

10.1101/2021.01.08.425793 ◽

2021 ◽

Author(s):

Lukasz Suprewicz ◽

Maxx Swoger ◽

Sarthak Gupta ◽

Ewelina Piktel ◽

Fitzroy F Byfield ◽

...

Keyword(s):

Cell Types ◽

Cell Entry ◽

Spike Protein ◽

Intermediate Filament Protein ◽

Surface Binding ◽

Angiotensin Converting Enzyme 2 ◽

Virus Like Particles ◽

Direct Binding ◽

Filament Protein

Infection of human cells by pathogens, including SARS-CoV-2, typically proceeds by cell surface binding to a crucial receptor. In the case of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) has been identified as a necessary receptor, but not all ACE2-expressing cells are equally infected, suggesting that other extracellular factors are involved in host cell invasion by SARS-CoV-2. Vimentin is an intermediate filament protein that is increasingly recognized as being present on the extracellular surface of a subset of cell types, where it can bind to and facilitate pathogens' cellular uptake. Here, we present evidence that extracellular vimentin might act as a critical component of the SARS-CoV-2 spike protein-ACE2 complex in mediating SARS-CoV-2 cell entry. We demonstrate direct binding between vimentin and SARS-CoV-2 virus-like particles coated with the SARS-CoV-2 spike protein and show that antibodies against vimentin block in vitro SARS-CoV-2 pseudovirus infection of ACE2-expressing cell lines. Our results suggest new therapeutic strategies for preventing and slowing SARS-CoV-2 infection, focusing on targeting cell host surface vimentin.

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