Comprehensive Virtual Screening of the Antiviral Potentialities of Marine Polycyclic Guanidine Alkaloids against SARS-CoV-2 (COVID-19)

The huge global expansion of the COVID-19 pandemic caused by the novel SARS-corona virus-2 is an extraordinary public health emergency. The unavailability of specific treatment against SARS-CoV-2 infection necessitates the focus of all scientists in this direction. The reported antiviral activities of guanidine alkaloids encouraged us to run a comprehensive in silico binding affinity of fifteen guanidine alkaloids against five different proteins of SARS-CoV-2, which we investigated. The investigated proteins are COVID-19 main protease (Mpro) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and a non-structural protein (nsp10) (PDB ID: 6W4H). The binding energies for all tested compounds indicated promising binding affinities. A noticeable superiority for the pentacyclic alkaloids particularly, crambescidin 786 (5) and crambescidin 826 (13) has been observed. Compound 5 exhibited very good binding affinities against Mpro (ΔG = −8.05 kcal/mol), nucleocapsid phosphoprotein (ΔG = −6.49 kcal/mol), and nsp10 (ΔG = −9.06 kcal/mol). Compound 13 showed promising binding affinities against Mpro (ΔG = −7.99 kcal/mol), spike glycoproteins (ΔG = −6.95 kcal/mol), and nucleocapsid phosphoprotein (ΔG = −8.01 kcal/mol). Such promising activities might be attributed to the long ω-fatty acid chain, which may play a vital role in binding within the active sites. The correlation of c Log P with free binding energies has been calculated. Furthermore, the SAR of the active compounds has been clarified. The Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) studies were carried out in silico for the 15 compounds; most examined compounds showed optimal to good range levels of ADMET aqueous solubility, intestinal absorption and being unable to pass blood brain barrier (BBB), non-inhibitors of CYP2D6, non-hepatotoxic, and bind plasma protein with a percentage less than 90%. The toxicity of the tested compounds was screened in silico against five models (FDA rodent carcinogenicity, carcinogenic potency TD50, rat maximum tolerated dose, rat oral LD50, and rat chronic lowest observed adverse effect level (LOAEL)). All compounds showed expected low toxicity against the tested models. Molecular dynamic (MD) simulations were also carried out to confirm the stable binding interactions of the most promising compounds, 5 and 13, with their targets. In conclusion, the examined 15 alkaloids specially 5 and 13 showed promising docking, ADMET, toxicity and MD results which open the door for further investigations for them against SARS-CoV-2.

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Comprehensive Virtual Screening of the Antiviral Potentialities of Marine Polycyclic Guanidine Alkaloids against SARS-CoV-2 (Covid-19)

10.26434/chemrxiv.13335899.v1 ◽

2020 ◽

Author(s):

Amr El-Demerdash ◽

Ahmed M. Metwaly ◽

Tarek Mohamed Abd El-Aziz4 ◽

Ibrahim H. Eissa ◽

James D. Stockand

Keyword(s):

In Silico ◽

Active Sites ◽

Aqueous Solubility ◽

Maximum Tolerated Dose ◽

Vital Role ◽

Binding Energies ◽

Binding Affinities ◽

Structural Protein ◽

Fatty Acid Chain ◽

Guanidine Alkaloids

A comprehensive in silico binding affinity of fifteen guanidine alkaloids against five different proteins of SARS-CoV-2 has been investigated. The investigated proteins are COVID-19 main protease (Mpro) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and non-structural protein (nsp10) (PDB ID: 6W4H). The binding energies for all tested compounds indicated promising binding affinities. A noticeable superiority for the pentacyclic alkaloids particularly, crambescidin 786 (5) and crambescidin 826 (13) have been observed. Compound 5 exhibited very good binding affinities against Mpro (ΔG = -8.05 kcal/mol), nucleocapsid phosphoprotein (ΔG = -6.49 kcal/mol), and nsp10 (ΔG = -9.06 kcal/mol). Compound 13 showed promising binding affinities against Mpro (ΔG = -7.99 kcal/mol), spike glycoproteins (ΔG = -6.95 kcal/mol), and nucleocapsid phosphoprotein (ΔG = -8.01 kcal/mol). Such promising activities might be attributed to the long ω-fatty acid chain, which may play a vital role in binding within the active sites. The ADMET studies were carried out in silico for the 15 compounds, all examined compounds (except compounds 8 and 15) have low or very low BBB penetration levels. Compounds 1, 5, 6, 9, 12 and 13 showed optimal range levels of ADMET aqueous solubility. Compounds 1, 2, 3, 8, and 15 were predicted to have good intestinal absorption levels, while compounds 4, 7, 9, 10, and 14 showed moderate absorption levels. All examined alkaloids (except the bicyclic compound 8) were predicted not to be inhibitors of CYP2D6, non-hepatotoxic, and bind plasma protein with a percentage less than 90%. The toxicity of the tested compounds was screened in silico against five models (FDA rodent carcinogenicity, carcinogenic potency TD50, rat maximum tolerated dose, rat oral LD50 and rat chronic LOAEL). All compounds showed expected low toxicity against the tested models.

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Comprehensive Virtual Screening of the Antiviral Potentialities of Marine Polycyclic Guanidine Alkaloids against SARS-CoV-2 (Covid-19)

10.26434/chemrxiv.13335899 ◽

2020 ◽

Author(s):

Amr El-Demerdash ◽

Ahmed M. Metwaly ◽

Tarek Mohamed Abd El-Aziz4 ◽

Ibrahim H. Eissa ◽

James D. Stockand

Keyword(s):

In Silico ◽

Active Sites ◽

Aqueous Solubility ◽

Maximum Tolerated Dose ◽

Vital Role ◽

Binding Energies ◽

Binding Affinities ◽

Structural Protein ◽

Fatty Acid Chain ◽

Guanidine Alkaloids

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In silico Discovery of Resveratrol Analogues as Potential Agents in Treatment of Metabolic Disorders

Current Pharmaceutical Design ◽

10.2174/1381612825666191029095252 ◽

2019 ◽

Vol 25 (35) ◽

pp. 3776-3783

Author(s):

Nebojša Pavlović ◽

Maja Đanić ◽

Bojan Stanimirov ◽

Svetlana Goločorbin-Kon ◽

Karmen Stankov ◽

...

Keyword(s):

In Silico ◽

Metabolic Disorders ◽

Partial Agonist ◽

Aqueous Solubility ◽

Structural Similarity ◽

Data Bank ◽

Docking Studies ◽

Binding Energies ◽

Molegro Virtual Docker ◽

Ppar Γ

Background: Resveratrol was demonstrated to act as partial agonist of PPAR-γ receptor, which opens up the possibility for its use in the treatment of metabolic disorders. Considering the poor bioavailability of resveratrol, particularly due to its low aqueous solubility, we aimed to identify analogues of resveratrol with improved pharmacokinetic properties and higher binding affinities towards PPAR-γ. Methods: 3D structures of resveratrol and its analogues were retrieved from ZINC database, while PPAR-γ structure was obtained from Protein Data Bank. Docking studies were performed using Molegro Virtual Docker software. Molecular descriptors relevant to pharmacokinetics were calculated from ligand structures using VolSurf+ software. Results: Using structural similarity search method, 56 analogues of resveratrol were identified and subjected to docking analyses. Binding energies were ranged from -136.69 to -90.89 kcal/mol, with 16 analogues having higher affinities towards PPAR-γ in comparison to resveratrol. From the calculated values of SOLY descriptor, 23 studied compounds were shown to be more soluble in water than resveratrol. However, only two tetrahydroxy stilbene derivatives, piceatannol and oxyresveratrol, had both better solubility and affinity towards PPAR-γ. These compounds also had more favorable ADME profile, since they were shown to be more metabolically stable and wider distributed in body than resveratrol. Conclusion: Piceatannol and oxyresveratrol should be considered as potential lead compounds for further drug development. Although experimental validation of obtained in silico results is required, this work can be considered as a step toward the discovery of new natural and safe drugs in treatment of metabolic disorders.

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In Silico Screening for Natural Ligands to Non-Structural Nsp7 Conformers of Coronaviruses

10.26434/chemrxiv.12952115.v1 ◽

2020 ◽

Author(s):

Rafael Blasco ◽

Julio Coll

Keyword(s):

In Silico ◽

Chemical Properties ◽

Structural Similarity ◽

Binding Pocket ◽

Binding Affinities ◽

Structural Protein ◽

Autodock Vina ◽

Natural Ligands ◽

Final Optimization

The non-structural protein 7 (nsp7) of Severe Acute Respiratory Syndrome (SARS) coronaviruses was selected as a new target to potentially interfere with viral replication. The nsp7s are one of the most conserved, unique and small coronavirus proteins having a critical, yet intriguing participation on the replication of the long viral RNA genome after complexing with nsp8 and nsp12. Despite the difficulties of having no previous binding pocket, two high-throughput virtual blind screening of 158240 natural compounds > 400 Da by AutoDock Vina against nsp7.1ysy identified 655 leads displaying predicted binding affinities between 10 to 1100 nM. The leads were then screened against 14 available conformations of nsp7 by both AutoDock Vina and seeSAR programs employing different binding score algorithms, to identify 20 consensus top-leads. Further in silico predictive analysis of physiological and toxicity ADMET criteria (chemical properties, adsorption, metabolism, toxicity) narrowed top-leads to a few drug-like ligands many of them showing steroid-like structures. A final optimization by search for structural similarity to the top drug-like ligand that were also commercially available, yielded a collection of predicted novel ligands with ~100-fold higher-affinity whose antiviral activity may be experimentally validated. Additionally, these novel nsp7-interacting ligands and/or their further optimized derivatives, may offer new tools to investigate the intriguing role of nsp7 on replication of coronaviruses.

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In silico studies of bioactive compounds from selected African plants with inhibitory activity against nitric oxide synthase and arginase implicated in asthma

Egyptian Journal of Medical Human Genetics ◽

10.1186/s43042-021-00175-8 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Haruna Isiyaku Umar ◽

Tolulope Peter Saliu ◽

Sunday Solomon Josiah ◽

Adeola Ajayi ◽

Jamilu Bala Danjuma

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Bioactive Compounds ◽

In Silico ◽

Active Sites ◽

Binding Energies ◽

Protein Database ◽

In Silico Studies ◽

Nos Inhibitors ◽

Oxide Synthase

Abstract Background It is a known fact that arginine is a common substrate for arginase and nitric oxide synthase (NOS). However, an imbalance between both enzymes could lead to a change in airway responses. Reports suggest that increased activities of both enzymes could lead to airway hyper-responsiveness. Thus, the requests for NOS inhibitors that can also inhibit arginase as the elevated activities of both enzymes have detrimental consequence on airways in asthma. Bioactive compounds from Azadirachta indica, Crinum glaucum, and Mangifera indica are documented for anti-inflammatory, immunomodulatory, anti-histaminic, smooth-muscle relaxants, and anti-allergic potentials. However, the mechanisms of action of these bioactive compounds in conferring the aforementioned protections are not well characterized. The objective of this present study is to assess in silico inhibitory potentials of these bioactive compounds against NOS and arginase via binding at their active sites. The crystal structures of NOS and arginase were retrieved from the protein database, while the bioactive compounds were retrieved from PubChem. Drug-likeness of the selected bioactive compounds was assessed using DruLiTo software. The successful compounds were docked with active sites of enzymes using AutoDock Vina docking software, and the docked complexes were analyzed using LigPlot and protein-ligand profiler web server. Results The findings of the study revealed that the bioactive compounds from A. indica, C. glaucum, and M. indica were able to interact with the active sites of NOS and arginase with the exception of gallic acid (from M. indica) and nimbandiol (from A. indica); these compounds showed differential binding energies (kcal/mol) and a number of them had higher binding energies than l-arginine when docked with NOS. Conclusion Conclusively, the in silico analysis proposes that these compounds could prove to be probable anti-asthmatic drugs.

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Zingiber officinale: Ayurvedic Uses of the Plant and In Silico Binding Studies of Selected Phytochemicals With Mpro of SARS-CoV-2

Natural Product Communications ◽

10.1177/1934578x211031766 ◽

2021 ◽

Vol 16 (10) ◽

pp. 1934578X2110317

Author(s):

Rownak Jahan ◽

Alok K. Paul ◽

Tohmina A. Bondhon ◽

Anamul Hasan ◽

Khoshnur Jannat ◽

...

Keyword(s):

Chlorogenic Acid ◽

In Silico ◽

Three Dimensional ◽

Zingiber Officinale ◽

Binding Energies ◽

Binding Affinities ◽

Binding Studies ◽

High Binding ◽

Main Protease ◽

In Silico Studies

Among the large number of plants that are part of the Ayurvedic system of medicine in India and Bangladesh, Zingiber officinale Roscoe (Zingiberaceae), or ginger in English, holds a special place and is often referred to as “Mahaushadha” (great medicine) and “Vishvabhesaja” (worldwide or universal herb) to signify its special status. The plant and particularly its rhizomes are used both in the raw and dry form for the relief of a multitude of disorders. Since a number of these disorders occur in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it was of interest to perform in silico studies (molecular docking) to evaluate the binding affinities of a number of constituents of Zingiber officinale with the 3C-like protease or main protease (Mpro) of SARS-CoV-2, which plays an essential role in the cleavage of viral polyproteins and subsequent viral replication. Our studies indicated that 2 of the compounds present in ginger, namely, chlorogenic acid and hesperidin, had high binding affinities for Mpro with predicted binding energies of −7.5 and −8.3 kcal/mol. The two-dimensional and three-dimensional interactions also showed that, while chlorogenic acid interacts with one of the His41 amino acids of the catalytic dyad of Mpro, hesperidin interacts with the other amino acid Cys145, which can account for their predicted high binding energies and, therefore, possibly can inhibit Mpro activity. Taken together, our findings indicate that ginger, besides alleviating the symptoms induced by SARS-CoV-2, may also play a role in inhibiting the virus.

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In silico screening of hundred phytocompounds of ten medicinal plants as potential inhibitors of nucleocapsid phosphoprotein of COVID-19: An approach to prevent virus assembly

10.21203/rs.3.rs-30484/v1 ◽

2020 ◽

Author(s):

Rajan Rolta ◽

Rohitash Yadav ◽

Deeksha Salaria ◽

Anuradha Sourirajan ◽

Kamal Dev

Keyword(s):

Medicinal Plants ◽

Active Sites ◽

Rna Binding ◽

Virus Assembly ◽

Specific Treatment ◽

Binding Domain ◽

Binding Energies ◽

Receptor Protein ◽

Aloe Emodin ◽

Rna Binding Domain

Abstract Currently, there is no specific treatment to cure COVID-19. Many medicinal plants have antiviral, antioxidant, antibacterial, antifungal, anticancer, wound healing etc. Therefore, the aim of the current study was to screen for potent inhibitors of N-terminal domain (NTD) of nucleocapsid phosphoproteinof SARS-CoV-2. The structure of NTD of RNA binding domain of nucleocapsid phosphoprotein of SARS coronavirus 2 was retrieved from the Protein Data Bank (PDB 6VYO)and the structures of 100 different phytocompoundswere retrieved from Pubchem. The receptor protein and ligands were prepared using Schrodinger’s Protein Preparation Wizard. Molecular docking was done by using the Schrodinger’s maestro 12.0 software. Drug likeness and toxicity of active phytocompounds was predicted by using Swiss adme, admetSAR and protox II online servers. We have identified three potential active sites (named as A, B, C) on receptor protein for efficient binding of the phytocompounds. We found that, among 100 phytocompounds, emodin, aloe-emodin, anthrarufin, alizarine, and dantron of Rheum emodi showed good binding affinity at all the three active sites of RNA binding domain of nucleocapsid phosphoprotein of COVID-19.The binding energies of emodin, aloe-emodin, anthrarufin, alizarine, and dantron were -8.299 , -8.508, -8.456, -8.441, and -8.322 Kcal mol-1 respectively (site A), -7.714, -6.433, -6.354, -6.598, and -6.99 Kcal mol-1 respectively (site B), and -8.299, 8.508, 8.538, 8.841, and 8.322 Kcal mol-1 respectively (site C).All the active phytocompounds follows the drug likeness properties, non-carcinogenic, and non-toxic. Theses phytocompounds (alone or in combination) could be developed into effective therapy against COVID-19.

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In Silico Investigation on the Interaction of Chiral Phytochemicals from Opuntia ficus-indica with SARS-CoV-2 Mpro

Symmetry ◽

10.3390/sym13061041 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1041

Author(s):

Caterina Vicidomini ◽

Valentina Roviello ◽

Giovanni N. Roviello

Keyword(s):

In Silico ◽

Quinic Acid ◽

Antiviral Drugs ◽

Binding Energies ◽

Binding Affinities ◽

Opuntia Ficus Indica ◽

Web Based ◽

Protein Targets ◽

Main Protease ◽

In Silico Studies

Opuntia ficus-indica is a cactaceous plant native to America but, nowadays, widely found worldwide, having been the most common domesticated species of cactus grown as a crop plant in semiarid and arid parts of the globe, including several Mediterranean basin countries. Opuntia ficus-indica can be regarded as a medicinal plant, being source of numerous bioactive phytochemicals such as vitamins, polyphenols, and amino acids. The urgent need for therapeutic treatments for the COronaVIrus Disease 19 (COVID-19), caused by the Severe Acute Respiratory Syndrome (SARS)-Coronavirus (CoV)-2, justifies the great attention currently being paid not only to repurposed antiviral drugs, but also to natural products and herbal medications. In this context, the anti-COVID-19 utility of Opuntia ficus-indica as source of potential antiviral drugs was investigated in this work on the basis of the activity of some of its phytochemical constituents. The antiviral potential was evaluated in silico in docking experiments with Mpro, i.e., the main protease of SARS-CoV-2, that is one of the most investigated protein targets of therapeutic strategies for COVID-19. By using two web-based molecular docking programs (1-Click Mcule and COVID-19 Docking Server), we found, for several flavonols and flavonol glucosides isolated from Opuntia ficus-indica, good binding affinities for Mpro, and in particular, binding energies lower than −7.0 kcal/mol were predicted for astragalin, isorhamnetin, isorhamnetin 3-O-glucoside, 3-O-caffeoyl quinic acid, and quercetin 5,4′-dimethyl ether. Among these compounds, the chiral compound astragalin showed in our in silico studies the highest affinity for Mpro (−8.7 kcal/mol) and also a low toxicity profile, emerging, thus, as an interesting protease inhibitor candidate for anti-COVID-19 strategies.

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Ruthenium Complexes for 1- and 2-Photon Photodynamic Therapy: From In Silico Prediction to In Vivo Applications

10.26434/chemrxiv.11767995 ◽

2020 ◽

Author(s):

Johannes Karges ◽

Shi Kuang ◽

Federica Maschietto ◽

Olivier Blacque ◽

Ilaria Ciofini ◽

...

Keyword(s):

Photodynamic Therapy ◽

In Silico ◽

Aqueous Solubility ◽

The Body ◽

Photon Absorption ◽

Multicellular Tumor Spheroids ◽

Spectral Window ◽

Photon Excitation ◽

Polypyridine Complexes

<div>The use of photodynamic therapy (PDT) against cancer has received increasing attention overthe recent years. However, the application of the currently approved photosensitizers (PSs) is somehow limited by their poor aqueous solubility, aggregation, photobleaching and slow clearance from the body. To overcome these limitations, there is a need for the development of new classes of PSs with ruthenium(II) polypyridine complexes currently gaining momentum. However, these compounds generally lack significant absorption in the biological spectral window, limiting their application to treat deep-seated or large tumors. To overcome this drawback, ruthenium(II) polypyridine complexes designed in silico with (E,E’)-4,4´-bisstyryl 2,2´-bipyridine ligands showed impressive 1- and 2-Photon absorption up to a magnitude higher than the ones published so far. While non-toxic in the dark, these compounds were found phototoxic in various 2D monolayer cells, 3D multicellular tumor spheroids and be able to eradicate a multiresistant tumor inside a mouse model upon clinically relevant 1-Photon and 2 Photon excitation.</div>

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On the Adsorption of Aspartate Derivatives to Calcite Surfaces in Aqueous Environment

10.26434/chemrxiv.11558430.v1 ◽

2020 ◽

Author(s):

Robert Stepic ◽

Lara Jurković ◽

Ksenia Klementyeva ◽

Marko Ukrainczyk ◽

Matija Gredičak ◽

...

Keyword(s):

Active Sites ◽

Realistic Model ◽

Binding Energies ◽

Inhibition Mechanism ◽

Aqueous Environment ◽

Binding Modes ◽

Carboxylate Groups ◽

Dissolved Ions ◽

Living Organisms ◽

Dynamics Simulations

In many living organisms, biomolecules interact favorably with various surfaces of calcium carbonate. In this work, we have considered the interactions of aspartate (Asp) derivatives, as models of complex biomolecules, with calcite. Using kinetic growth experiments, we have investigated the inhibition of calcite growth by Asp, Asp2 and Asp3.This entailed the determination of a step-pinning growth regime as well as the evaluation of the adsorption constants and binding free energies for the three species to calcite crystals. These latter values are compared to free energy profiles obtained from fully atomistic molecular dynamics simulations. When using a flat (104) calcite surface in the models, the measured trend of binding energies is poorly reproduced. However, a more realistic model comprised of a surface with an island containing edges and corners, yields binding energies that compare very well with experiments. Surprisingly, we find that most binding modes involve the positively charged, ammonium group. Moreover, while attachment of the negatively charged carboxylate groups is also frequently observed, it is always balanced by the aqueous solvation of an equal or greater number of carboxylates. These effects are observed on all calcite features including edges and corners, the latter being associated with dominant affinities to Asp derivatives. As these features are also precisely the active sites for crystal growth, the experimental and theoretical results point strongly to a growth inhibition mechanism whereby these sites become blocked, preventing further attachment of dissolved ions and halting further growth.

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