Virtual Screening of the Flavonoids Compounds with the SARS-CoV-2 3C-like Protease as the Lead Compounds for the COVID-19

As of 1st of September 2020, the COVID-19 pandemic has reached an unprecedented level of more than 25 million cases with more than 850,000 deaths. Moreover, all the drug candidates are still undergoing testing in clinical trials. In this regard, a breakthrough in drug design is neces-sary. One strategy to devise lead compounds is leveraging natural products as a lead source. Sever-al companies and research institutes are currently developing anti-SARS-CoV-2 lead from natural products. Flavonoids are well known as a class of antiviral compounds library. The objective of this research is to employ virtual screening methods for obtaining the best lead compounds from the library of flavonoid compounds. This research employed virtual screening methods that com-prised of downloading the protein and lead compound structures, QSAR analysis prediction, itera-tions of molecular docking simulation, and ADME-TOX simulation for toxicity prediction. The QSAR analysis found that the tested compounds have broad-spectrum antiviral activity, and some of them exhibit specific binding to the 3C-like Protease of the Coronavirus. Moreover, juglanin was found as the compound with the fittest binding with the Protease enzyme of SARS-CoV-2. Al-though most of the tested compounds are deemed toxic by the ADME-Tox test, further research should be conducted to comprehend the most feasible strategy to deliver the drug to the infected lung cells. The juglanin compound is selected as the fittest candidate as the SARS-CoV-2 lead compound in the tested flavonoid samples. However, further research should be conducted to observe the lead delivery method to the cell.Copyright © 2021 Bentham Science Publishers.

Molecular simulation of compounds from n-hexane fraction of Sonchus arvensis L. leaves as SARS-CoV-2 antiviral through inhibitor activity targeting strategic viral protein

Context: COVID-19 was caused by the spread and transmission of SARS-CoV-2 at the end of 2019 until now. The problem comes when antiviral drugs have not yet been found and patients infected with SARS-CoV-2 can trigger a cytokine storm condition due to the effects of viral replication. Indonesia has various kinds of medicinal plants, such as Sonchus arvensis L., which are used as medicinal plants. Aim(s): To analyze the activity of the inhibitor as SARS-CoV-2 antiviral agents from n-hexane fractions of S. arvensis leaves. Method(s): The sample was collected from GC-MS analysis, PubChem, and Protein Databank database, then drug-likeness identification using Lipinski Rule of Five server and bioactive prediction of bioactive compounds as inhibitor activity was conducted by Molinspiration server. Furthermore, the docking simulation was performed using PyRx 0.9.9 software to determine the binding activity, molecular interaction by Discovery Studio software to identify position and interaction type, 3D molecular visualization by PyMol 2.5. software, and dynamic by CABS-flex 2.0 server to predict interaction stability. Result(s): alpha-Amyrin and beta-amyrin from n-hexane fractions of S. arvensis leaves had activity as SARS-CoV-2 inhibitors through interactions on helicase, RdRp, Mpro, and RBD-Spike, both compounds had more negative binding affinity than control drug and can produce stable chemical bond interactions in the ligand-protein complexes. However, the results were merely computational, so they must be validated through an in vivo and in vitro research approach. Conclusion(s): Sonchus arvensis L. leaves were predicted to have SARS-CoV-2 antiviral through inhibitor activity by alpha-amyrin and beta-amyrin. Copyright © 2022 Journal of Pharmacy & Pharmacognosy Research.

Identification of Flavonoids of Kalanchoe Pinnata as Candidate Drugs for COVID-19 Gamma-Variant Treatment

Treatment of COVID-19 that is based on plants could be a more cost-effective therapy against the disease. Flavonoids, a group of compounds that have been observed to have various effects, including antiviral activity, were chosen as the candidate molecule for treatment of COVID-19. Kalanchoe Pinnata is one of the plants containing flavonoids that has been demonstrated to have antiviral activity. The structure of ACE2 and various flavonoids were retrieved and cleaned from unnecessary residues. The ACE2 structure was subjected to molecular docking in order to analyze the binding affinity. Following that, the ADME properties of each flavonoid were analyzed accordingly. The QSAR analysis was also performed for each type of flavonoid. Lastly, molecular dynamics simulation was conducted. All of the tested compounds were able to bind to human ACE2 and SARS-CoV-2 Spike protein, but were unable to compete with them as the binding affinity of the compounds to the protein were lower compared to ACE2-Spike interaction. The ADME and toxicity analysis showed that most of the ligands were able to be absorbed by the GI tract, but have low bioavailability. The compounds also cause no major toxicity effects and were able to be sufficiently distributed to the body. Molecular dynamics analysis also revealed that among the compounds, quercetin and rutin were able to interact with ACE2 and Spike protein stably. The QSAR analysis showed that friedelin, kaempferol, quercetin, and rutin are mostly non-toxic, but the high Cramer values indicate that there are no initial safety impressions for these molecules and could cause toxicity. In conclusion, quercetin and rutin have potential to be a candidate for COVID-19 drug development based on the in-silico predictions results obtained. Friedelin and Narcissin whose affinity to the proteins were relatively stronger but had unstable interactions from molecular dynamics simulation results, may also be a potential COVID-19 treatment with further investigation. However, further research is required to assess the effectiveness and also specially to measure the toxicity of the compounds. © 2022 Malaysian Journal of Fundamental and Applied Sciences.

A Computational Design of siRNA in SARS-CoV-2 Spike Glycoprotein Gene and Its Binding Capability toward mRNA

COVID-19 pandemic has no immediate ending in sight, and any significant increasing cases were observed worldwide. Currently, there are only two main strategies for developing COVID-19 drugs that predominantly use a proteomics-based approach, which are drug repurposing and herbal medicine strategies. However, a third strategy has existed, called small interfering RNA or siRNA, which is based on the transcriptomics approach. In the case of SARS-CoV-2 infection, it is expected to perform by silencing the viral gene, which brings the surface glycoprotein (S) gene responsible for SARS-CoV-2 viral attachment to the ACE2 receptor on the human host cell. This third approach applies a molecular simulation method comprising data retrieval, multiple sequence alignment, phylogenetic tree depiction, 2D/3D structure prediction, and RNA-RNA molecular docking. The expected results are the prediction of 2D and 3D structures of both siRNA and mRNA silenced S genes along with a complex as the result of a docking method formed by those silenced genes. An Insilco chemical interaction study was performed in testing siRNA and mRNA complex’s stability with the confirmation result of a stable complex which is expected to be formed before mRNA reaches the ribosome for the translation process. Thus, siRNA from the S gene could be considered a candidate for the COVID-19 therapeutic agent. © 2022, Gadjah Mada University. All rights reserved.

COMPUTATIONAL EXAMINATION OF FLAVONOID COMPOUNDS: UTILIZATION OF MOLECULAR SIMULATION TO DISCOVER DRUG CANDIDATES FOR COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the novel coronavirus disease 19 (COVID19) pandemic. Despite drugs had been deployed through intense research, none has been proven to cure the infection. Flavonoids, a natural substance, have been reported to exhibit various pharmaceutical and medical properties. The aim of this research is to discover lead compounds for covid-19 from flavonoid compounds through in silico study. Through computational examination, the potential of flavonoid compounds against SARS-CoV-2 has been examined and it shows that some flavonoids have potential against SARS-CoV-2. © 2022, Rasayan Journal of Chemistry, c/o Dr. Pratima Sharma. All rights reserved.

Bioactive compounds from mangosteen (Garcinia mangostana L.) as an antiviral agent via dual inhibitor mechanism against SARSCoV- 2: an in silico approach

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes COVID-19 which is responsible for respiratory illness infection in humans. The virus was first identified in China in 2019 and later spread to other countries worldwide. This study aims to identify the bioactive compounds from mangosteen (Garcinia mangostana L.) as an antiviral agent via dual inhibitor mechanisms against two SARS-CoV-2 proteases through the in silico approach. The three-dimensional structure of various bioactive compounds of mangosteen from the database was examined. Furthermore, all the target compounds were analyzed for drug, antiviral activity prediction, virtual screening, molecular interactions, and threedimensional structure visualization. It aimed to determine the potential of the bioactive compounds from mangosteen that can serve as antiviral agents to fight SARS-CoV-2. Results showed that the bioactive compounds from mangosteen have the prospective to provide antiviral agents that contradict the virus via dual inhibitory mechanisms. In summary, the binding of the various bioactive compounds from mangosteen results in low binding energy and is expected to have the ability to induce any activity of the target protein binding reaction. Therefore, it allows various bioactive compounds from mangosteen to act as dual inhibitory mechanisms for COVID-19 infection.

COVID-19 In Silico Drug with Zingiber officinale Natural Product Compound Library Targeting the M-pro Protein

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide pandemic. Ginger (Zingiber officinale) is a rhizome, which is commonly used for culinary and medicinal purposes. In Indonesia, ginger is taken as traditional medicine by processing it into a drink known as jamu. The present study aimed to assess and evaluate the bioactive compounds in ginger that can be used in drug design for treating COVID-19. The crystal structure of the SARS-CoV-2 main protease (M-pro) was generated from a protein sequence database, i.e., Protein Data Bank, and the bioactive compounds in ginger were derived from the existing compounds library. M-pro is involved in polyprotein synthesis, including viral maturation and nonstructural protein gluing, making it a potential antiviral target. Furthermore, the bioactive compounds in ginger were analyzed using Lipinski's rule of five to determine their drug-like molecular properties. Moreover, molecular docking analysis was conducted using the Python Prescription 0.8 (Virtual Screening Tool) software, and the interaction between SARS-CoV-2 M-pro and the bioactive compounds in ginger was extensively examined using the PyMOL software. Out all of the 16 bioactive compounds that were docked successfully, 4-gingerol, which has the lowest binding energy against SARS-CoV-2 M-pro, as per the virtual screening results, was proven to have the most potential as a viral inhibitor of SARS-CoV-2.

Potential vaccine targets for COVID-19 and phylogenetic analysis based on the nucleocapsid phosphoprotein of Indonesian SARS-CoV-2 isolates

Recently, the world is facing outbreaks of severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 and the number of infected patients is increasing every day. Researchers are doing their best to find the most effective treatment to tackle this deathly virus. Several approaches had been proposed to be tested in the lab for efficacy but none of them are qualified to be used as the treatment of the COVID-19. Therefore, this study aimed to design a vaccine based on epitope, which was obtained from the nucleocapsid phosphoprotein (N protein). 38 samples of SARS-CoV-2 isolates were retrieved from the GISAID Database and NCBI GenBank. These samples were used to check the evolutionary relationship of the SARS-CoV-2 and determine whether these nucleocapsid proteins are well-conserved with less or even no mutations occur at all, and whether there was any evolutionary relationship between the recent coronavirus with the previous coronavirus by conducting the phylogenetic analysis. Then, it is desirable to see the molecular interaction between the human BCR/FAB receptor with the predicted peptides through the molecular docking process. All of the peptides were generated by the IEDB analysis tools and have already been tested for antigenicity, so the one that was being docked is the peptide that has antigen properties. Based on the analysis that had been done, the PEP1 was recommended as an epitope-based peptide vaccine candidate to deal with the SARS-CoV-2 outbreaks. Copyright © 2020 THE AUTHOR(S).

Genetic variant of SARS-CoV-2 isolates in Indonesia: spike glycoprotein gene. (Special Issue: Coronaviruses and COVID-19- Past, Present, and Future.)

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a novel coronavirus and the primary causative agent of coronavirus disease 2019 (COVID-19), first occurred in China and rapidly spread worldwide. The government of the Republic of Indonesia confirmed its first two cases of COVID-19 in March 2020. COVID-19 is a serious illness with no efficacious antiviral medication or approved vaccine currently available. Therefore, there is a need to investigate the genome of SARS-CoV-2. In this study, we characterized SARS-CoV-2 spike glycoprotein genes from Indonesia to investigate their genetic composition and variability. Overall, ten SARS-CoV-2 spike glycoprotein gene sequences retrieved from GenBank (National Center for Biotechnology Information, USA) and the GISAID EpiCoV database (Germany) were compared. We analyzed nucleotide variants and amino acid changes using Molecular Evolutionary Genetics Analysis (MEGA) X and analyzed gene similarity using the LALIGN web server. Interestingly, we revealed several specific mutation sites, however, there were no significant changes in the genetic composition of SARS-CoV-2 spike glycoprotein genes, when compared to the Wuhan- Hu-1 isolate from China. However, this is a preliminary study and we recommend that molecular epidemiology and surveillance programs against COVID-19 in Indonesia be improved.

Natural products repurposing of the H5N1-based lead compounds for the most fit inhibitors against 3C-like protease of SARS-CoV-2

Context: COVID-19 pandemic has caused more than 2.7 million mortality worldwide. Although the COVID-19 vaccine has been developed, the amount is still limited, and very few countries have reached 'herd immunity' level. In this regard, imported and community infections is still happening in the world. In order to complement the vaccine rollout, the drug is still necessary. Up to now, all the COVID-19 drugs in the market are still in emergency use, and their clinical application is still under tight surveillance. Thus, a breakthrough in drug development is necessary. Based on an extensive protein crystallography experiment, it is known that the 3C-like protease of SARS-CoV-2 plays an important role in the pathogenicity of the virus. Several inhibitors have been developed for this protein, including remdesivir that served as the standard in this experiment. However, recent findings in the wet lab also showed possible significant bioactivities for the repurposed influenza, and human rhinovirus leads for SARS-CoV-2. Previous research has developed flavonoid-based leads as H5N1 virus inhibitors. Aims: To develop lead compounds to inhibit 3C-like protease of SARS-CoV-2 from the existing H5N1 leads. Methods: The ligands and protein were prepared with energy minimization and the "add protonation" procedure. Then, the QSAR analysis was conducted to determine whether the ligands fit as leads for the 3C-like protease SARS-CoV-2 inhibitor. Molecular docking simulation was deployed for the selected ligand toward the 3C-like protease enzyme. Moreover, the molecular dynamics simulation was devised to examine the protein flexibility of the protease ligands. Results: It was found that only 9 out of the 19 repurposed H5N1-leads elicited significant QSAR-based properties for general antivirus, influenza antivirus, and antihuman rhinovirus bioactivities. In this regard, the leads were screened further with molecular docking, in silico ADME-TOX prediction, and molecular dynamics methods. Based on the further screen, the ligands of M00009235 and M00006834 were selected as lead compounds for 3C-like protease SARS-CoV-2 inhibitors. Conclusions: The ligands of M00009235 and M00006834 were selected as the best leads for inhibiting 3C-like protease of SARS-CoV-2 based on the virtual screening methods.