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1.
J Ovarian Res ; 14(1): 126, 2021 Sep 27.
Article in English | MEDLINE | ID: covidwho-1440942

ABSTRACT

BACKGROUND: Infections by the SARS-CoV-2 virus causing COVID-19 are presently a global emergency. The current vaccination effort may reduce the infection rate, but strain variants are emerging under selection pressure. Thus, there is an urgent need to find drugs that treat COVID-19 and save human lives. Hence, in this study, we identified phytoconstituents of an edible vegetable, Bitter melon (Momordica charantia), that affect the SARS-CoV-2 spike protein. METHODS: Components of Momordica charantia were tested to identify the compounds that bind to the SARS-CoV-2 spike protein. An MTiOpenScreen web-server was used to perform docking studies. The Lipinski rule was utilized to evaluate potential interactions between the drug and other target molecules. PyMol and Schrodinger software were used to identify the hydrophilic and hydrophobic interactions. Surface plasmon resonance (SPR) was employed to assess the interaction between an extract component (erythrodiol) and the spike protein. RESULTS: Our in-silico evaluations showed that phytoconstituents of Momordica charantia have a low binding energy range, -5.82 to -5.97 kcal/mol. A docking study revealed two sets of phytoconstituents that bind at the S1 and S2 domains of SARS-CoV-2. SPR showed that erythrodiol has a strong binding affinity (KD = 1.15 µM) with the S2 spike protein of SARS-CoV-2. Overall, docking, ADME properties, and SPR displayed strong interactions between phytoconstituents and the active site of the SARS-CoV-2 spike protein. CONCLUSION: This study reveals that phytoconstituents from bitter melon are potential agents to treat SARS-CoV-2 viral infections due to their binding to spike proteins S1 and S2.


Subject(s)
COVID-19/drug therapy , Momordica charantia/chemistry , Plant Extracts/pharmacology , Spike Glycoprotein, Coronavirus/genetics , Binding Sites/drug effects , COVID-19/genetics , COVID-19/virology , Humans , Hydrophobic and Hydrophilic Interactions/drug effects , Molecular Docking Simulation , Oleanolic Acid/analogs & derivatives , Oleanolic Acid/chemistry , Oleanolic Acid/pharmacology , Plant Extracts/chemistry , Protein Binding/drug effects , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Surface Plasmon Resonance
2.
Int J Biol Macromol ; 183: 2248-2261, 2021 Jul 31.
Article in English | MEDLINE | ID: covidwho-1260750

ABSTRACT

The recent emergence of the novel coronavirus (SARS-CoV-2) has resulted in a devastating pandemic with global concern. However, to date, there are no regimens to prevent and treat SARS-CoV-2 virus. There is an urgent need to identify novel leads with anti-viral properties that impede viral pathogenesis in the host system. Esculentoside A (EsA), a saponin isolated from the root of Phytolacca esculenta, is known to exhibit diverse pharmacological properties, especially anti-inflammatory activity. To our knowledge, SARS-CoV-2 uses angiotensin converting enzyme 2 (ACE2) to enter host cells. This is mediated through the proteins of SARS-CoV-2, especially the spike glycoprotein receptor binding domain. Thus, our primary goal is to prevent virus replication and binding to the host, which allows us to explore the efficiency of EsA on key surface drug target proteins using the computational biology paradigm approach. Here, the anti-coronavirus activity of EsA in vitro and its potential mode of inhibitory action on the S-protein of SARS-CoV-2 were investigated. We found that EsA inhibited the HCoV-OC43 coronavirus during the attachment and penetration stage. Molecular docking results showed that EsA had a strong binding affinity with the spike glycoprotein from SARS-CoV-2. The results of the molecular dynamics simulation revealed that EsA had higher stable binding with the spike protein. These results demonstrated that Esculentoside A can act as a spike protein blocker to inhibit SARS-CoV-2. Considering the poor bioavailability and low toxicity of EsA, it is suitable as novel lead for the inhibitor against binding interactions of SARS-CoV-2 of S-protein and ACE2.


Subject(s)
Angiotensin-Converting Enzyme 2 , Antiviral Agents , COVID-19/drug therapy , Molecular Docking Simulation , Molecular Dynamics Simulation , Oleanolic Acid/analogs & derivatives , SARS-CoV-2 , Saponins , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cell Line, Tumor , Coronavirus OC43, Human/chemistry , Coronavirus OC43, Human/metabolism , Humans , Oleanolic Acid/chemistry , Oleanolic Acid/pharmacology , SARS-CoV-2/chemistry , SARS-CoV-2/physiology , Saponins/chemistry , Saponins/pharmacology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
3.
J Med Chem ; 64(9): 5632-5644, 2021 05 13.
Article in English | MEDLINE | ID: covidwho-1193564

ABSTRACT

To develop antiviral therapeutics against human coronavirus (HCoV) infections, suitable coronavirus drug targets and corresponding lead molecules must be urgently identified. Here, we describe the discovery of a class of HCoV inhibitors acting on nsp15, a hexameric protein component of the viral replication-transcription complexes, endowed with immune evasion-associated endoribonuclease activity. Structure-activity relationship exploration of these 1,2,3-triazolo-fused betulonic acid derivatives yielded lead molecule 5h as a strong inhibitor (antiviral EC50: 0.6 µM) of HCoV-229E replication. An nsp15 endoribonuclease active site mutant virus was markedly less sensitive to 5h, and selected resistance to the compound mapped to mutations in the N-terminal part of HCoV-229E nsp15, at an interface between two nsp15 monomers. The biological findings were substantiated by the nsp15 binding mode for 5h, predicted by docking. Hence, besides delivering a distinct class of inhibitors, our study revealed a druggable pocket in the nsp15 hexamer with relevance for anti-coronavirus drug development.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 229E, Human/drug effects , Coronavirus 229E, Human/enzymology , Endoribonucleases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Oleanolic Acid/analogs & derivatives , Viral Nonstructural Proteins/antagonists & inhibitors , Virus Replication/drug effects , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Cell Line , Dose-Response Relationship, Drug , Endoribonucleases/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Microbial Sensitivity Tests , Models, Molecular , Oleanolic Acid/chemical synthesis , Oleanolic Acid/chemistry , Oleanolic Acid/pharmacology , Viral Nonstructural Proteins/metabolism
4.
Mol Divers ; 25(3): 1889-1904, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1046729

ABSTRACT

Saikosaponins are major biologically active triterpenoids, usually as glucosides, isolated from Traditional Chinese Medicines (TCM) such as Bupleurum spp., Heteromorpha spp., and Scrophularia scorodonia with their antiviral and immunomodulatory potential. This investigation presents molecular docking, molecular dynamics simulation, and free energy calculation studies of saikosaponins as adjuvant therapy in the treatment for COVID19. Molecular docking studies for 23 saikosaponins on the crystal structures of the extracellular domains of human lnterleukin-6 receptor (IL6), human Janus Kinase-3 (JAK3), and dehydrogenase domain of Cylindrospermum stagnale NADPH-oxidase 5 (NOX5) were performed, and selected protein-ligand complexes were subjected to 100 ns molecular dynamics simulations. The molecular dynamics trajectories were subjected to free energy calculation by the MM-GBSA method. Molecular docking and molecular dynamics simulation studies revealed that IL6 in complex with Saikosaponin_U and Saikosaponin_V, JAK3 in complex with Saikosaponin_B4 and Saikosaponin_I, and NOX5 in complex with Saikosaponin_BK1 and Saikosaponin_C have good docking and molecular dynamics profiles. However, the Janus Kinase-3 is the best interacting partner for the saikosaponin compounds. The network pharmacology analysis suggests saikosaponins interact with the proteins CAT Gene CAT (Catalase) and Checkpoint kinase 1 (CHEK1); both of these enzymes play a major role in cell homeostasis and DNA damage during infection, suggesting a possible improvement in immune response toward COVID-19.


Subject(s)
COVID-19/drug therapy , Molecular Docking Simulation , Molecular Dynamics Simulation , Oleanolic Acid/analogs & derivatives , Saponins/pharmacology , Humans , Oleanolic Acid/metabolism , Oleanolic Acid/pharmacology , Oleanolic Acid/therapeutic use , Protein Domains , Saponins/metabolism , Saponins/therapeutic use
5.
Future Med Chem ; 12(19): 1743-1757, 2020 10.
Article in English | MEDLINE | ID: covidwho-662472

ABSTRACT

At the end of 2019, a novel virus causing severe acute respiratory syndrome to spread globally. There are currently no effective drugs targeting SARS-CoV-2. In this study, based on the analysis of numerous references and selected methods of computational chemistry, the strategy of integrative structural modification of small molecules with antiviral activity into potential active complex molecules has been presented. Proposed molecules have been designed based on the structure of triterpene oleanolic acid and complemented by structures characteristic of selected anti-COVID therapy assisted drugs. Their pharmaceutical molecular parameters and the preliminary bioactivity were calculated and predicted. The results of the above analyses show that among the designed complex substances there are potential antiviral agents directed mainly on SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Repositioning , Pneumonia, Viral/drug therapy , Antiviral Agents/chemistry , COVID-19 , Cardiovascular Agents/chemistry , Cardiovascular Agents/pharmacology , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacology , Humans , Oleanolic Acid/chemistry , Oleanolic Acid/pharmacology , Pandemics , SARS-CoV-2
6.
Phytomedicine ; 85: 153277, 2021 May.
Article in English | MEDLINE | ID: covidwho-643666

ABSTRACT

The world is witnessing a difficult time. The race of developing a new coronavirus (COVID-19) vaccine is becoming more urgent. Many preliminary studies on the pathophysiology of COVID-19 patients have provided some clues to treat this pandemic. However, no suitable treatment has found yet. Various symptoms of patients infected with COVID-19 indicated the importance of immune regulation in the human body. Severe cases admitted to the intensive care unit showed high level of pro-inflammatory cytokines which enhanced the disease severity. Acute Respiratory Distress Syndrome (ARDS) in COVID-19 patients is another critical factor of disease severity and mortality. So, Immune modulation is the only way of regulating immune system. Nigella sativa has been used for medicinal purposes for centuries. The components of this plant are known for its intense immune-regulatory, anti-inflammatory, and antioxidant benefits in obstructive respiratory disorders. A molecular docking study also gave evidences that N. sativa decelerates COVID-19 and might give the same or better results than the FDA approved drugs. The aim of this review was to investigate the possible immune-regulatory effects of N. sativa on COVID-19 pandemic. Our review found N. sativa's Thymoquinone, Nigellidine, and α-hederin can be a potential influencer in reinforcing the immune response on molecular grounds.


Subject(s)
COVID-19/drug therapy , Immune System/drug effects , Nigella sativa/chemistry , Plant Extracts/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Benzoquinones/pharmacology , Drug Evaluation, Preclinical , Humans , Molecular Docking Simulation , Oleanolic Acid/pharmacology , Pandemics , SARS-CoV-2/drug effects
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