scholarly journals PLANT SUBSTANCES AS POTENTIAL SOURCE OF ORIGINAL ANTI-VIRUS AGENTS

2021 ◽  
Vol 3 ◽  
pp. 83-96
Author(s):  
S.M. Adekenov ◽  
◽  
Keyword(s):  
New Drugs ◽  
Spike Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Antiviral Compounds ◽  
Potential Source ◽  
Structure Activity ◽  
Docking Method ◽  
Relationship Of ◽  
Plant Substances ◽  
Molecular Docking Method

This article summarizes the literature data and the results of our own studies on the search for antiviral compounds based on terpenoids, flavonoids, alkaloids. New bimolecular and ketoamide derivatives based on sesquiterpene γ-lactones arglabin, grossheimin and α-santonin were synthesized in quantitative yields up to 80%. The molecular docking method was used to study the “structure-activity” relationship of natural compounds and their derivatives in relation to SARS-Cov-2. The results obtained in silico demonstrated that sesquiterpene γ-lactones and their derivatives inhibit the SARS-Cov-2 spike protein and proteases, as well as the angiotensin-converting enzyme 2. The identified molecules can be considered as candidates for the development of new drugs with antiviral activity on their basis.

scholarly journals Structural Optimization and Structure–Activity Relationship of 4-Thiazolidinone Derivatives as Novel Inhibitors of Human Dihydroorotate Dehydrogenase

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2780
Author(s):  
Fanxun Zeng ◽  
Lina Quan ◽  
Guantian Yang ◽  
Tiantian Qi ◽  
Letian Zhang ◽  
...  
Keyword(s):  
Binding Mode ◽  
Structure Activity Relationship ◽  
Immunosuppressive Drugs ◽  
Activity Relationship ◽  
Dihydroorotate Dehydrogenase ◽  
Structure Activity ◽  
Docking Method ◽  
Ic50 Values ◽  
Relationship Of ◽  
Molecular Docking Method

Human dihydroorotate dehydrogenase (hDHODH), one of the attractive targets for the development of immunosuppressive drugs, is also a potential target of anticancer drugs and anti-leukemic drugs. The development of promising hDHODH inhibitors is in high demand. Based on the unique binding mode of our previous reported 4-thiazolidinone derivatives, via molecular docking method, three new series 4-thiazolidinone derivatives were designed and synthesized as hDHODH inhibitors. The preliminary structure–activity relationship was investigated. Compound 9 of biphenyl series and compound 37 of amide series displayed IC50 values of 1.32 μM and 1.45 μM, respectively. This research will provide valuable reference for the research of new structures of hDHODH inhibitors.

scholarly journals Synthesis of oxadiazole-2-oxide derivatives as potential drug candidates for schistosomiasis targeting SjTGR

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Gongming Li ◽  
Qingqing Guo ◽  
Chao Feng ◽  
Huan Chen ◽  
Wenjiao Zhao ◽  
...  
Keyword(s):  
Schistosoma Japonicum ◽  
Inhibitory Activity ◽  
Pyridine Ring ◽  
New Drugs ◽  
Wild Type ◽  
Drug Candidates ◽  
Structure Activity ◽  
Docking Method ◽  
Antigen Protein ◽  
Thioredoxin Glutathione Reductase

Abstract Background Schistosomiasis is a chronic parasitic disease that affects millions of people’s health worldwide. Because of the increasing drug resistance to praziquantel (PZQ), which is the primary drug for schistosomiasis, developing new drugs to treat schistosomiasis is crucial. Oxadiazole-2-oxides have been identified as potential anti-schistosomiasis reagents targeting thioredoxin glutathione reductase (TGR). Methods In this work, one of the oxadiazole-2-oxides derivatives furoxan was used as the lead compound to exploit a series of novel furoxan derivatives for studying inhibitory activity against both recombinant Schistosoma japonicum TGR containing selenium (rSjTGR-Sec) and soluble worm antigen protein (SWAP) containing wild-type Schistosoma japonicum TGR (wtSjTGR), in order to develop a new leading compound for schistosomiasis. Thirty-nine novel derivatives were prepared to test their activity toward both enzymes. The docking method was used to detect the binding site between the active molecule and SjTGR. The structure–activity relationship (SAR) of these novel furoxan derivatives was preliminarily analyzed. Results It was found that several new derivatives, including compounds 6a–6d, 9ab, 9bd and 9be, demonstrated greater activity toward rSjTGR-Sec or SWAP containing wtSjTGR than did furoxan. Interestingly, all intermediates bearing hydroxy (6a–6d) showed excellent inhibitory activity against both enzymes. In particular, compound 6d with trifluoromethyl on a pyridine ring was found to have much higher inhibition toward both rSjTGR-Sec (half-maximal inhibitory concentration, IC50,7.5nM) and SWAP containing wtSjTGR (IC50 55.8nM) than furoxan. Additionally, the docking method identified the possible matching sites between 6d and Schistosoma japonicum TGR (SjTGR), which theoretically lends support to the inhibitory activity of 6d. Conclusion The data obtained herein showed that 6d with trifluoromethyl on a pyridine ring could be a valuable leading compound for further study.

scholarly journals In-Silico evidence for two receptors based strategy of SARS-CoV-2

2020 ◽  
Author(s):  
Edoardo Milanetti ◽  
Mattia Miotto ◽  
Lorenzo Di Rienzo ◽  
Michele Monti ◽  
Giorgio Gosti ◽  
...  
Keyword(s):  
Protein Complexes ◽  
General Procedure ◽  
Spike Protein ◽  
Geometrical Shape ◽  
Upper Airways ◽  
Protein Surfaces ◽  
Angiotensin Converting Enzyme 2 ◽  
Shape Complementarity ◽  
Dual Strategy ◽  
Relationship Of

We propose a novel numerical method able to determine efficiently and effectively the relationship of complementarity between portions of protein surfaces. This innovative and general procedure, based on the representation of the molecular iso-electron density surface in terms of 2D Zernike polynomials, allows the rapid and quantitative assessment of the geometrical shape complementarity between interacting proteins, that was unfeasible with previous methods. We first tested the method with a large dataset of known protein complexes obtaining an overall area under the ROC curve of 0.76 in the blind recognition of binding sites and then applied it to investigate the features of the interaction between the Spike protein of SARS-CoV-2 and human cellular receptors. Our results indicate that SARS-CoV-2 uses a dual strategy: its spike protein could also interact with sialic acid receptors of the cells in the upper airways, in addition to the known interaction with Angiotensin-converting enzyme 2.

scholarly journals In-Silico Evidence for a Two Receptor Based Strategy of SARS-CoV-2

2021 ◽  
Vol 8 ◽  
Author(s):  
Edoardo Milanetti ◽  
Mattia Miotto ◽  
Lorenzo Di Rienzo ◽  
Madhu Nagaraj ◽  
Michele Monti ◽  
...  
Keyword(s):  
General Procedure ◽  
Spike Protein ◽  
Geometrical Shape ◽  
Upper Airways ◽  
Protein Surfaces ◽  
Angiotensin Converting Enzyme 2 ◽  
Shape Complementarity ◽  
Dual Strategy ◽  
Sialic Acid Receptors ◽  
Relationship Of

We propose a computational investigation on the interaction mechanisms between SARS-CoV-2 spike protein and possible human cell receptors. In particular, we make use of our newly developed numerical method able to determine efficiently and effectively the relationship of complementarity between portions of protein surfaces. This innovative and general procedure, based on the representation of the molecular isoelectronic density surface in terms of 2D Zernike polynomials, allows the rapid and quantitative assessment of the geometrical shape complementarity between interacting proteins, which was unfeasible with previous methods. Our results indicate that SARS-CoV-2 uses a dual strategy: in addition to the known interaction with angiotensin-converting enzyme 2, the viral spike protein can also interact with sialic-acid receptors of the cells in the upper airways.

scholarly journals Differential Interactions Between Human ACE2 and Spike RBD of SARS-CoV-2 Variants of Concern

2021 ◽  
Author(s):  
Seonghan Kim ◽  
Yi Liu ◽  
Zewei Lei ◽  
Jeffrey Dicker ◽  
Yiwei Cao ◽  
...  
Keyword(s):  
New Drugs ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Angiotensin Converting Enzyme 2 ◽  
Microscale Thermophoresis ◽  
The Us ◽  
Alpha Beta ◽  
Smd Simulations ◽  
High Infectivity

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the current coronavirus disease 2019 (COVID-19) pandemic. It is known that the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 interacts with the human angiotensin-converting enzyme 2 (ACE2) receptor, initiating the entry of SARS-CoV-2. Since its emergence, a number of SARS-CoV-2 variants have been reported, and the variants that show high infectivity are classified as the variants of concern according to the US CDC. In this study, we performed both all-atom steered molecular dynamics (SMD) simulations and microscale thermophoresis (MST) experiments to characterize the binding interactions between ACE2 and RBD of all current variants of concern (Alpha, Beta, Gamma, and Delta) and two variants of interest (Epsilon and Kappa). We report that the RBD of the Alpha (N501Y) variant requires the highest amount of force initially to be detached from ACE2 due to the N501Y mutation in addition to the role of N90-glycan, followed by Beta/Gamma (K417N/T, E484K, and N501Y) or Delta (L452R and T478K) variant. Among all variants investigated in this work, the RBD of the Epsilon (L452R) variant is relatively easily detached from ACE2. Our results combined SMD simulations and MST experiments indicate what makes each variant more contagious in terms of RBD and ACE2 interactions. This study could help develop new drugs to inhibit SARS-CoV-2 entry effectively.

scholarly journals Pharmacological Significance of Hesperidin and Hesperetin, Two Citrus Flavonoids, as Promising Antiviral Compounds for Prophylaxis Against and Combating COVID-19

2021 ◽  
Vol 16 (10) ◽  
pp. 1934578X2110425
Author(s):  
Pawan K. Agrawal ◽  
Chandan Agrawal ◽  
Gerald Blunden
Keyword(s):  
Docking Studies ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Citrus Fruits ◽  
Angiotensin Converting Enzyme 2 ◽  
Antiviral Compounds ◽  
Early Proteins ◽  
Citrus Flavonoids ◽  
Pharmacological Significance ◽  
Multiple Regions

Hesperidin and hesperetin are flavonoids that are abundantly present as constituents of citrus fruits. These compounds have attracted attention as several computational methods, mostly docking studies, have shown that hesperidin may bind to multiple regions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (spike protein, angiotensin-converting enzyme 2, and proteases). Hesperidin has a low binding energy, both with the SARS-CoV-2 “spike” protein responsible for internalization, and also with the “PLpro” and “Mpro” responsible for transforming the early proteins of the virus into the complex responsible for viral replication. This suggests that these flavonoids could act as prophylactic agents by blocking several mechanisms of viral infection and replication, and thus helping the host cell to resist viral attack.

scholarly journals Synthesis of Oxadiazole-2-Oxide Derivatives as Potential Drug Candidates for Schistosomiasis Targeted on SjTGR

2020 ◽  
Author(s):  
dequn sun ◽  
Gongming Li ◽  
Qingqing Guo ◽  
Chao Feng ◽  
Huan Chen ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Pyridine Ring ◽  
Inhibitory Concentration ◽  
New Drugs ◽  
Wild Type ◽  
Drug Candidates ◽  
Structure Activity ◽  
Docking Method ◽  
Antigen Protein ◽  
Thioredoxin Glutathione Reductase

Abstract Background: Schistosomiasis is a chronic parasitic disease that affects the health of millions people worldwide. Developing new drugs to treat schistosomiasis is crucial because of the increasing drug resistant to praziquantel (PZQ), the main drug for schistosomiasis. Oxadiazole-2-oxides have been identified as a potential anti-schistosomiasis reagent targeted to thioredoxin glutathione reductase (TGR).Methods: In this work, one of the oxadiazole-2-oxides derivatives furoxan was used as the lead compound to exploit series of novel furoxan derivatives for studying inhibitory activity against both recombinant Schistosoma japonicumi TGR containing selenium (rSjTGR-Sec) and soluble worm antigen protein (SWAP) containing wild type Schistosoma japonicumi TGR (wtSjTGR) in order to develop new leading compound for schistosomasis. Thirty nine novel derivatives were prepared to test their activity to both rSjTGR-Sec and SWAP containing wtSjTGR. The docking method was used to detect the bind sites between active molecule and SjTGR; The structure-activity relationship (SAR) of these novel furoxan derivatives was preliminarily analyzed.Results: It was founded that several new derivatives such as compounds 6a-6d, 9ab, 9bd, 9be have better activity to rSjTGR-Sec or SWAP containing wtSjTGR than furoxan. Interestingly, all intermediates bearing hydroxy (6a-6d) showed excellent inhibitory activity to both rSjTGR-Sec and SWAP containing wtSjTGR especially, compound 6d with trifluoromethyl on pyridine ring was found to have much higher inhibition to both rSjTGR-Sec (half-maximal inhibitory concentration, IC50,7.5nM) and SWAP containing wtSjTGR (IC50 55.8nM) than furoxan (4µM to SWAP containing wtSjTGR and 5.87µM to rSjTGR-Sec). Additionally, the docking method revealed the matching sites between 6d and Schistosoma japonicumi TGR (SjTGR), which theoretically lends support to inhibitory activity of 6d. Conclusion: The data obtained herein showed preliminarily that 6d with trifluoromethyl on pyridine ring could be a valuable leading compound for further study.

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