Nature Potential for COVID-19: Targeting SARS-CoV-2 Mpro Inhibitor with Bioactive Compound

10.26434/chemrxiv.14112515.v2 ◽

2021 ◽

Author(s):

Kaushik Kumar Bharadwaj ◽

Tanmay Sarkar ◽

Arabinda Ghosh ◽

Debabrat Baishya ◽

Bijuli Rabha ◽

...

Keyword(s):

Binding Energy ◽

Antiviral Activity ◽

Binding Free Energy ◽

Bioactive Compound ◽

Binding Pocket ◽

Stable Conformation ◽

Lipinski’S Rule ◽

Macrolactin A

Corona viruses were first identified in 1931 and SARS-CoV-2 is the most recent. COVID-19 is a pandemic that put most of the world on lockdown and the search for therapeutic drugs is still on-going. Therefore, this study uses in silico screening to identify natural bioactive compounds from fruits, herbaceous plants and marine invertebrates that are able to inhibit protease activity in SARS-CoV-2(PDB: 6LU7). We have used various screening strategies such as drug likeliness, antiviral activity value prediction, molecular docking, ADME (absorption, distribution, metabolism, and excretion), molecular dynamics (MD) simulation and MM/GBSA (molecular mechanics/generalized born and surface area continuum solvation). 17 compounds were shortlisted using Lipinski’s rule. 5 compounds revealed significantly good predicted antiviral activity values and out of them only 2 compounds, Macrolactin A and Stachyflin, showed good binding energy values of -9.22 and -8.00 kcal/mol within the binding pocket, catalytic residues (HIS 41 and CYS 145) of Mpro. These two compounds were further analyzed for their ADME properties. The ADME evaluation of these 2 compounds suggested that they could be effective as therapeutic agents for developing drugs for clinical trials. MD simulations showed that protein-ligand complexes of Macrolactin A and Stachyflin were stable for 100 nano seconds. The MM/GBSA calculations of Mpro – Macrolactin A complex indicated higher binding free energy (-42.58 ± 6.35 kcal/mol) with Mpro protein target receptor (6LU7). DCCM and PCA analysis on the residual movement in the MD trajectories confirmed the good stability on Macrolactin A bound state of 6LU7. This signify the stable conformation of 6LU7 with high binding energy with Macrolactin A. Thus, this study showed that Macrolactin A could be an effective therapeutical agent for SARS-CoV-2protease (6LU7) inhibition. Additional in vitro and in vivo validations are needed to determine efficacy and dose of Macrolactin A in biological systems.

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Nature Potential for COVID-19: Targeting SARS-CoV-2 Mpro Inhibitor with Bioactive Compound

10.26434/chemrxiv.14112515.v1 ◽

2021 ◽

Author(s):

Kaushik Kumar Bharadwaj ◽

Tanmay Sarkar ◽

Arabinda Ghosh ◽

Debabrat Baishya ◽

Bijuli Rabha ◽

...

Keyword(s):

Binding Energy ◽

Antiviral Activity ◽

Binding Free Energy ◽

Bioactive Compound ◽

Binding Pocket ◽

Stable Conformation ◽

Lipinski’S Rule ◽

Macrolactin A

Corona viruses were first identified in 1931 and SARS-CoV-2 is the most recent. COVID-19 is a pandemic that put most of the world on lockdown and the search for therapeutic drugs is still on-going. Therefore, this study uses in silico screening to identify natural bioactive compounds from fruits, herbaceous plants and marine invertebrates that are able to inhibit protease activity in SARS-CoV-2(PDB: 6LU7). We have used various screening strategies such as drug likeliness, antiviral activity value prediction, molecular docking, ADME (absorption, distribution, metabolism, and excretion), molecular dynamics (MD) simulation and MM/GBSA (molecular mechanics/generalized born and surface area continuum solvation). 17 compounds were shortlisted using Lipinski’s rule. 5 compounds revealed significantly good predicted antiviral activity values and out of them only 2 compounds, Macrolactin A and Stachyflin, showed good binding energy values of -9.22 and -8.00 kcal/mol within the binding pocket, catalytic residues (HIS 41 and CYS 145) of Mpro. These two compounds were further analyzed for their ADME properties. The ADME evaluation of these 2 compounds suggested that they could be effective as therapeutic agents for developing drugs for clinical trials. MD simulations showed that protein-ligand complexes of Macrolactin A and Stachyflin were stable for 100 nano seconds. The MM/GBSA calculations of Mpro – Macrolactin A complex indicated higher binding free energy (-42.58 ± 6.35 kcal/mol) with Mpro protein target receptor (6LU7). DCCM and PCA analysis on the residual movement in the MD trajectories confirmed the good stability on Macrolactin A bound state of 6LU7. This signify the stable conformation of 6LU7 with high binding energy with Macrolactin A. Thus, this study showed that Macrolactin A could be an effective therapeutical agent for SARS-CoV-2protease (6LU7) inhibition. Additional in vitro and in vivo validations are needed to determine efficacy and dose of Macrolactin A in biological systems.

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In Silico Guided Drug Repurposing to Combat SARS-CoV-2 by Targeting Mpro, the Key Virus Specific Protease

10.26434/chemrxiv.12030345 ◽

2020 ◽

Author(s):

Ruchi Rani ◽

Ankur Singh ◽

Akshay Pareek ◽

Shailly Tomar

Keyword(s):

Binding Energy ◽

Large Population ◽

Drug Repurposing ◽

Binding Pocket ◽

World Health ◽

Binding Modes ◽

Specific Protease ◽

Health Organization

The reemergence of SARS-CoV named, as SARS-CoV-2 has been highly infectious and able to infect a large population around the globe. The World Health Organization (WHO) has declared this SARS-CoV-2 associated Coronavirus Disease 2019 (COVID-19) as pandemic. SARS-CoV-2 genome is translated into polyproteins and has been processed by its protease enzymes. 3CLprotease is named as main protease (Mpro) enzyme which cleaves nsp4-nsp16. This crucial role of Mpro makes this enzyme a prime and promising antiviral target. The drug repurposing is a fast alternative method than the discovery of novel antiviral molecules. We have used high-throughput virtual screening approach to examine FDA approved LOPAC1280 library against Mpro. Primary screening have identified few potential drug molecule for the target among which 10 molecules were studied further. Molecular docking of selected molecules was done to detailed study about their binding energy and binding modes. Positively, Etoposide, BMS_195614, KT185, Idarubicin and WIN_62577 were found interacting with substrate binding pocket of Mpro with higher binding energy. These molecules are being advanced by our group for in vitro and in vivo testing to study the efficacy of identified drugs. As per our understanding, these molecules have the potential to efficiently interrupt the viral life cycle and may reduce or eliminate the expeditious outspreading of SARS-CoV-2.

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Computational Approach for Covalent Lead Identification against Spike Glycoprotein of SARS-CoV-2

10.21203/rs.3.rs-702450/v1 ◽

2021 ◽

Author(s):

Ravi BHUSHAN ◽

Pawan K Dubey ◽

Akhtar Ali ◽

Harshit Dwivedi ◽

Anuj Kumar ◽

...

Keyword(s):

Binding Energy ◽

Virtual Screening ◽

Binding Affinity ◽

Spike Glycoprotein ◽

Lipinski’S Rule ◽

Discovery Studio ◽

Synthetic Molecules ◽

Docking Approach

Abstract Background: A global outbreak of coronavirus disease 19 (COVID-19) led researchers to investigate various active compounds that can inhibit the replication of SARS-CoV2 (severe acute respiratory syndrome coronavirus 2). The present work targets to evaluate small covalent synthetic molecules through a virtual screening and docking approach that can efficiently inhibit Spike Glycoprotein of SARS CoV2.Methods: We retrieved around 50,000 small covalent synthetic molecules through the American chemical society (CAS) database. The initial evaluation of these synthetic molecules depends on the ADMET screening. A Lipinski's Rule of Five (RO5) was also applied to find whether the drug met the criteria of good bioavailability. Then, the further selection was made through virtual screening using BIOVIA Discovery Studio. Further, comparison among top hits was performed via a docking approach based on the binding energy (kcal/mol) calculated using the AutoDock Vina plugin and Patch Dock-like docking engines. Finally, the selected top five molecules were compared for their binding efficiency with reference drugs like Favipiravir, Chloroquine, Ribavirin, Hydroxychloroquine (approved by the FDA), and molecules with better binding affinity than reference drugs was selected.Results: In the first tier of selection, 215 molecules were screened out, satisfying all the necessary conditions of RO5 and ADMET. Among 215 molecules screened, only 203 molecules were stable in structure to undergo the second tier of target-based virtual screening. Further, based upon the LibDock score generated by virtual screening, the top five molecules with the highest LibD score were selected. Molecular docking of these five selected compounds reveals compound2 (3-ethyl-5-propyladamantan-1-amine) with the best binding energy. Furthermore, we compared the binding affinity of 3-ethyl-5-propyladamantan-1-amine with reported drugs that show 3-ethyl-5-propyladamantan-1-amine as the most promising ligand efficient hydrogen bond interactions with amino acid residues of protein which provides more excellent stability in the docked region of the protein with efficient binding energy as compared to the reference molecule. Moreover, Compound2 also has a high oral bioavailability, non-mutagenicity, non-toxicity and follows all RO5 criteria.Conclusion: Thus, it has potential as an antiviral covalent synthetic molecule that may prevent the replication of spike protein. These findings are just preliminary selection to facilitate the upcoming tests from in vivo and in vitro studies.

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In Silico Guided Drug Repurposing to Combat SARS-CoV-2 by Targeting Mpro, the Key Virus Specific Protease

10.26434/chemrxiv.12030345.v1 ◽

2020 ◽

Author(s):

Ruchi Rani ◽

Ankur Singh ◽

Akshay Pareek ◽

Shailly Tomar

Keyword(s):

Binding Energy ◽

Large Population ◽

Drug Repurposing ◽

Binding Pocket ◽

World Health ◽

Binding Modes ◽

Specific Protease ◽

Health Organization

The reemergence of SARS-CoV named, as SARS-CoV-2 has been highly infectious and able to infect a large population around the globe. The World Health Organization (WHO) has declared this SARS-CoV-2 associated Coronavirus Disease 2019 (COVID-19) as pandemic. SARS-CoV-2 genome is translated into polyproteins and has been processed by its protease enzymes. 3CLprotease is named as main protease (Mpro) enzyme which cleaves nsp4-nsp16. This crucial role of Mpro makes this enzyme a prime and promising antiviral target. The drug repurposing is a fast alternative method than the discovery of novel antiviral molecules. We have used high-throughput virtual screening approach to examine FDA approved LOPAC1280 library against Mpro. Primary screening have identified few potential drug molecule for the target among which 10 molecules were studied further. Molecular docking of selected molecules was done to detailed study about their binding energy and binding modes. Positively, Etoposide, BMS_195614, KT185, Idarubicin and WIN_62577 were found interacting with substrate binding pocket of Mpro with higher binding energy. These molecules are being advanced by our group for in vitro and in vivo testing to study the efficacy of identified drugs. As per our understanding, these molecules have the potential to efficiently interrupt the viral life cycle and may reduce or eliminate the expeditious outspreading of SARS-CoV-2.

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Therapeutic Potentials of Syzygium fruticosum Fruit (Seed) Reflected into an Array of Pharmacological Assays and Prospective Receptors-Mediated Pathways

Life ◽

10.3390/life11020155 ◽

2021 ◽

Vol 11 (2) ◽

pp. 155

Author(s):

Jannatul Nasma Rupa Moni ◽

Md. Adnan ◽

Abu Montakim Tareq ◽

Md. Imtiazul Kabir ◽

A.S.M. Ali Reza ◽

...

Keyword(s):

Bioactive Compounds ◽

Integrated Approach ◽

Gas Chromatography Mass Spectrometry ◽

Clot Lysis ◽

Lipinski’S Rule ◽

Lysis Activity ◽

In Silico Studies ◽

Immobility Time

Syzygium fruticosum (SF), a valuable Bangladeshi fruit, is considered an alternative therapeutic agent. Mainly, seeds are used as nutritional phytotherapy to ease physical and mental status by preventing chronic diseases. Here, we scrutinized the S. fruticosum seed’s fundamental importance in traditional medicine by following an integrated approach combining in vivo, in vitro, and in silico studies. The SF was fractionated with different solvents, and the ethyl acetate fraction of SF (EaF-SF) was further studied. Mice treated with EaF-SF (200 and 400 mg/kg) manifested anxiolysis evidenced by higher exploration in elevated plus maze and hole board tests. Similarly, a dose-dependent drop of immobility time in a forced swimming test ensured significant anti-depressant activity. Moreover, higher dose treatment exposed reduced exploratory behaviour resembling decreased movement and prolonged sleeping latency with a quick onset of sleep during the open field and thiopental-induced sleeping tests, respectively. In parallel, EaF-SF significantly (p < 0.001) and dose-dependently suppressed acetic acid and formalin-induced pain in mice. Also, a noteworthy anti-inflammatory activity and a substantial (p < 0.01) clot lysis activity (thrombolytic) was observed. Gas chromatography-mass spectrometry (GC–MS) analysis resulted in 49 bioactive compounds. Among them, 12 bioactive compounds with Lipinski’s rule and safety confirmation showed strong binding affinity (molecular docking) against the receptors of each model used. To conclude, the S. fruticosum seed is a prospective source of health-promoting effects that can be an excellent candidate for preventing degenerative diseases.

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Antiviral activity of Mulberroside C against enterovirus A71 in vitro and in vivo

European Journal of Pharmacology ◽

10.1016/j.ejphar.2021.174204 ◽

2021 ◽

pp. 174204

Author(s):

Yiming Cao ◽

En Lei ◽

Lei Li ◽

Jin Ren ◽

Xiaoyang He ◽

...

Keyword(s):

Antiviral Activity ◽

Enterovirus A71

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Filociclovir Is an Active Antiviral Agent against Ocular Adenovirus Isolates In Vitro and in the Ad5/NZW Rabbit Ocular Model

Pharmaceuticals ◽

10.3390/ph14040294 ◽

2021 ◽

Vol 14 (4) ◽

pp. 294

Author(s):

Eric G. Romanowski ◽

Islam T. M. Hussein ◽

Steven C. Cardinale ◽

Michelle M. Butler ◽

Lucas R. Morin ◽

...

Keyword(s):

Antiviral Activity ◽

Topical Treatment ◽

Antiviral Agent ◽

Human Adenovirus ◽

Treatment Groups ◽

Ocular Infections ◽

The Mean ◽

Eye Infection

Presently, there is no FDA- or EMA-approved antiviral for the treatment of human adenovirus (HAdV) ocular infections. This study determined the antiviral activity of filociclovir (FCV) against ocular HAdV isolates in vitro and in the Ad5/NZW rabbit ocular model. The 50% effective concentrations (EC50) of FCV and cidofovir (CDV) were determined for several ocular HAdV types using standard plaque reduction assays. Rabbits were topically inoculated in both eyes with HAdV5. On day 1, the rabbits were divided into four topical treatment groups: (1) 0.5% FCV 4x/day × 10 d; (2) 0.1% FCV 4x/day × 10 d; (3) 0.5% CDV 2x/day × 7 d; (4) vehicle 4x/day × 10 d. Eyes were cultured for virus on days 0, 1, 3, 4, 5, 7, 9, 11, and 14. The resulting viral eye titers were determined using standard plaque assays. The mean in vitro EC50 for FCV against tested HAdV types ranged from 0.50 to 4.68 µM, whereas those treated with CDV ranged from 0.49 to 30.3 µM. In vivo, compared to vehicle, 0.5% FCV, 0.1% FCV, and 0.5% CDV produced lower eye titers, fewer numbers of positive eye cultures, and shorter durations of eye infection. FCV demonstrated anti-adenovirus activity in vitro and in vivo.

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Possible Future Monoclonal Antibody (mAb)-Based Therapy against Arbovirus Infections

BioMed Research International ◽

10.1155/2013/838491 ◽

2013 ◽

Vol 2013 ◽

pp. 1-21 ◽

Cited By ~ 12

Author(s):

Giuseppe Sautto ◽

Nicasio Mancini ◽

Giacomo Gorini ◽

Massimo Clementi ◽

Roberto Burioni

Keyword(s):

Monoclonal Antibody ◽

Monoclonal Antibodies ◽

Side Effects ◽

Antiviral Activity ◽

The Other ◽

Viral Escape ◽

Passive Immunotherapy ◽

Medical Need

More than 150 arboviruses belonging to different families are known to infect humans, causing endemic infections as well as epidemic outbreaks. Effective vaccines to limit the occurrence of some of these infections have been licensed, while for the others several new immunogens are under development mostly for their improvements concerning safety and effectiveness profiles. On the other hand, specific and effective antiviral drugs are not yet available, posing an urgent medical need in particular for emergency cases. Neutralizing monoclonal antibodies (mAbs) have been demonstrated to be effective in the treatment of several infectious diseases as well as in preliminaryin vitroandin vivomodels of arbovirus-related infections. Given their specific antiviral activity as well-tolerated molecules with limited side effects, mAbs could represent a new therapeutic approach for the development of an effective treatment, as well as useful tools in the study of the host-virus interplay and in the development of more effective immunogens. However, before their use as candidate therapeutics, possible hurdles (e.g., Ab-dependent enhancement of infection, occurrence of viral escape variants) must be carefully evaluated. In this review are described the main arboviruses infecting humans and candidate mAbs to be possibly used in a future passive immunotherapy.

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Template-dependent biosynthesis of poly(G)·poly(C) and its antiviral activity in vitro and in vivo

Antiviral Research ◽

10.1016/s0166-3542(98)00018-7 ◽

1998 ◽

Vol 38 (2) ◽

pp. 131-140 ◽

Cited By ~ 1

Author(s):

M.A Surzhik ◽

L.M Vilner ◽

A.L Katchurin ◽

A.L Timkovskii

Keyword(s):

Antiviral Activity

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