scholarly journals In Silico Screening of Potential Phytocompounds from Several Herbs against SARS-CoV-2 Indian Delta Variant B.1.617.2 to Inhibit the Spike Glycoprotein Trimer

2022 ◽  
Vol 12 (2) ◽  
pp. 665
Author(s):  
Muruganantham Bharathi ◽  
Bhagavathi Sundaram Sivamaruthi ◽  
Periyanaina Kesika ◽  
Subramanian Thangaleela ◽  
Chaiyavat Chaiyasut
Keyword(s):  
The United States ◽  
Inhibitory Effect ◽  
Binding Affinities ◽  
Standard Drug ◽  
Houttuynia Cordata ◽  
Future Drug ◽  
Strong Inhibitory Effect ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Shed Light

In October 2020, the SARS-CoV-2 B.1.617 lineage was discovered in India. It has since become a prominent variant in several Indian regions and 156 countries, including the United States of America. The lineage B.1.617.2 is termed the delta variant, harboring diverse spike mutations in the N-terminal domain (NTD) and the receptor-binding domain (RBD), which may heighten its immune evasion potentiality and cause it to be more transmissible than other variants. As a result, it has sparked substantial scientific investigation into the development of effective vaccinations and anti-viral drugs. Several efforts have been made to examine ancient medicinal herbs known for their health benefits and immune-boosting action against SARS-CoV-2, including repurposing existing FDA-approved anti-viral drugs. No efficient anti-viral drugs are available against the SARS-CoV-2 Indian delta variant B.1.617.2. In this study, efforts were made to shed light on the potential of 603 phytocompounds from 22 plant species to inhibit the Indian delta variant B.1.617.2. We also compared these compounds with the standard drug ceftriaxone, which was already suggested as a beneficial drug in COVID-19 treatment; these compounds were compared with other FDA-approved drugs: remdesivir, chloroquine, hydroxy-chloroquine, lopinavir, and ritonavir. From the analysis, the identified phytocompounds acteoside (−7.3 kcal/mol) and verbascoside (−7.1 kcal/mol), from the plants Clerodendrum serratum and Houttuynia cordata, evidenced a strong inhibitory effect against the mutated NTD (MT-NTD). In addition, the phytocompounds kanzonol V (−6.8 kcal/mol), progeldanamycin (−6.4 kcal/mol), and rhodoxanthin (−7.5 kcal/mol), from the plant Houttuynia cordata, manifested significant prohibition against RBD. Nevertheless, the standard drug, ceftriaxone, signals less inhibitory effect against MT-NTD and RBD with binding affinities of −6.3 kcal/mol and −6.5 kcal/mol, respectively. In this study, we also emphasized the pharmacological properties of the plants, which contain the screened phytocompounds. Our research could be used as a lead for future drug design to develop anti-viral drugs, as well as for preening the Siddha formulation to control the Indian delta variant B.1.617.2 and other future SARS-CoV-2 variants.

scholarly journals Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Vicky Mody ◽  
Joanna Ho ◽  
Savannah Wills ◽  
Ahmed Mawri ◽  
Latasha Lawson ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Dynamics Simulation ◽  
Simulation Studies ◽  
Inhibitory Effects ◽  
Major Threat ◽  
Main Protease ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Computational Molecular Modeling

AbstractEmerging outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is a major threat to public health. The morbidity is increasing due to lack of SARS-CoV-2 specific drugs. Herein, we have identified potential drugs that target the 3-chymotrypsin like protease (3CLpro), the main protease that is pivotal for the replication of SARS-CoV-2. Computational molecular modeling was used to screen 3987 FDA approved drugs, and 47 drugs were selected to study their inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme in vitro. Our results indicate that boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin exhibited inhibitory effect towards 3CLpro enzymatic activity. The 100 ns molecular dynamics simulation studies showed that ivermectin may require homodimeric form of 3CLpro enzyme for its inhibitory activity. In summary, these molecules could be useful to develop highly specific therapeutically viable drugs to inhibit the SARS-CoV-2 replication either alone or in combination with drugs specific for other SARS-CoV-2 viral targets.

scholarly journals Lead Identification to Clinical Candidate Selection

2014 ◽  
Vol 20 (1) ◽  
pp. 101-111 ◽  
Author(s):  
R. Jeffrey Neitz ◽  
Steven Chen ◽  
Frantisek Supek ◽  
Vince Yeh ◽  
Danielle Kellar ◽  
...  
Keyword(s):  
San Francisco ◽  
Chagas Disease ◽  
Colorimetric Assay ◽  
The United States ◽  
Ergosterol Biosynthesis ◽  
Screening Methods ◽  
Ergosterol Biosynthesis Inhibitors ◽  
Approved Drugs ◽  
The University ◽  
Fda Approved Drugs

Chagas disease affects 8 million people worldwide and remains a main cause of death due to heart failure in Latin America. The number of cases in the United States is now estimated to be 300,000, but there are currently no Food and Drug Administration (FDA)–approved drugs available for patients with Chagas disease. To fill this gap, we have established a public-private partnership between the University of California, San Francisco and the Genomics Institute of the Novartis Research Foundation (GNF) with the goal of delivering clinical candidates to treat Chagas disease. The discovery phase, based on the screening of more than 160,000 compounds from the GNF Academic Collaboration Library, led to the identification of new anti-Chagas scaffolds. Part of the screening campaign used and compared two screening methods, including a colorimetric-based assay using Trypanosoma cruzi expressing β-galactosidase and an image-based, high-content screening (HCS) assay using the CA-I/72 strain of T. cruzi. Comparing molecules tested in both assays, we found that ergosterol biosynthesis inhibitors had greater potency in the colorimetric assay than in the HCS assay. Both assays were used to inform structure-activity relationships for antiparasitic efficacy and pharmacokinetics. A new anti– T. cruzi scaffold derived from xanthine was identified, and we describe its development as lead series.

scholarly journals Multi-Targeted Approaches and Drug Repurposing Reveal Possible SARS-CoV-2 Inhibitors

Vaccines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 24
Author(s):  
Khalid Mashay Alanazi ◽  
Mohammad Abul Farah ◽  
Yan-Yan Hor
Keyword(s):  
Experimental Validation ◽  
Computational Analysis ◽  
Treatment Options ◽  
Drug Repurposing ◽  
Binding Affinities ◽  
Normal Model ◽  
Inhibitory Potential ◽  
Us Fda ◽  
Approved Drugs ◽  
Fda Approved Drugs

The COVID-19 pandemic caused by SARS-CoV-2 is unprecedented in recent memory owing to the non-stop escalation in number of infections and deaths in almost every country of the world. The lack of treatment options further worsens the scenario, thereby necessitating the exploration of already existing US FDA-approved drugs for their effectiveness against COVID-19. In the present study, we have performed virtual screening of nutraceuticals available from DrugBank against 14 SARS-CoV-2 proteins. Molecular docking identified several inhibitors, two of which, rutin and NADH, displayed strong binding affinities and inhibitory potential against SARS-CoV-2 proteins. Further normal model-based simulations were performed to gain insights into the conformational transitions in proteins induced by the drugs. The computational analysis in the present study paves the way for experimental validation and development of multi-target guided inhibitors to fight COVID-19.

scholarly journals Identification of Drugs Targeting Multiple Viral and Human Proteins Using Computational Analysis for Repurposing Against COVID-19

2020 ◽  
Author(s):  
Sugandh Kumar ◽  
Pratima Kumari ◽  
Geetanjali Agnihotri ◽  
Preethy VijayKumar ◽  
Shaheerah Khan ◽  
...  
Keyword(s):  
Interaction Network ◽  
Viral Proteins ◽  
Inhibitory Effect ◽  
Host Proteins ◽  
Disease Manifestation ◽  
Protein Protein Interaction ◽  
Human Proteins ◽  
Approved Drugs ◽  
Viral Lifecycle ◽  
Fda Approved Drugs

<p>The SARS-CoV2 is a highly contagious pathogen that causes a respiratory disease named COVID-19. The COVID-19 was declared a pandemic by the WHO on 11th March 2020. It has affected about 5.38 million people globally (identified cases as on 24th May 2020), with an average lethality of ~3%. Unfortunately, there is no standard cure for the disease, although some drugs are under clinical trial. Thus, there is an urgent need of drugs for the treatment of COVID-19. The molecularly targeted therapies have proven their utility in various diseases such as HIV, SARS, and HCV. Therefore, a lot of efforts are being directed towards the identification of molecules that can be helpful in the management of COVID-19. </p> <p>In the current studies, we have used state of the art bioinformatics techniques to screen the FDA approved drugs against thirteen SARS-CoV2 proteins in order to identify drugs for quick repurposing. The strategy was to identify potential drugs that can target multiple viral proteins simultaneously. Our strategy originates from the fact that individual viral proteins play specific role in multiple aspects of viral lifecycle such as attachment, entry, replication, morphogenesis and egress and targeting them simultaneously will have better inhibitory effect.</p> <p>Additionally, we analyzed if the identified molecules can also affect the host proteins whose expression is differentially modulated during SARS-CoV2 infection. The differentially expressed genes (DEGs) were identified using analysis of NCBI-GEO data (GEO-ID: GSE-147507). A pathway and protein-protein interaction network analysis of the identified DEGs led to the identification of network hubs that may play important roles in SARS-CoV2 infection. Therefore, targeting such genes may also be a beneficial strategy to curb disease manifestation. We have identified 29 molecules that can bind to various SARS-CoV2 and human host proteins. We hope that this study will help researchers in the identification and repurposing of multipotent drugs, simultaneously targeting the several viral and host proteins, for the treatment of COVID-19.</p>

scholarly journals HIV protease inhibitors saquinavir and nelfinavir are potent inhibitors of cathepsin L activity: A potential treatment for COVID-19 patients

2020 ◽  
Author(s):  
Marcelo Freitas Montenegro ◽  
Yousef Al-Abed ◽  
Mingzhu He ◽  
Kevin J. Tracey ◽  
Timothy R. Billiar
Keyword(s):  
Clinical Trials ◽  
Cathepsin L ◽  
Inhibitory Effect ◽  
Host Cells ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Potential Treatment ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract The 2019 coronavirus disease pandemic (COVID-19) has mobilized efforts worldwide, and several ongoing clinical trials aimed at developing a drug-based treatment for its control. Cathepsin L is an endosomal cysteine protease that mediates the cleavage of the S1 subunit of the coronavirus surface spike glycoprotein. This cleavage is necessary for coronavirus entry into human host cells and viruses/host cell endosome membrane fusion. Therefore, cathepsin L is a potential target for the treatment of COVID-19 patients. In this report, we describe a previously unknown inhibitory effect of two FDA-approved drugs, saquinavir and nelfinavir, on human cathepsin L activity. Whether the pivotal role for cathepsin L in Sars-Cov-2 infection described in vitro can be translated to humans, our results support immediate clinical trials of saquinavir or nelfinavir as a potential treatment for COVID-19 patients.

scholarly journals Identification of Drugs Targeting Multiple Viral and Human Proteins Using Computational Analysis for Repurposing Against COVID-19

2020 ◽  
Author(s):  
Sugandh Kumar ◽  
Pratima Kumari ◽  
Geetanjali Agnihotri ◽  
Preethy VijayKumar ◽  
Shaheerah Khan ◽  
...  
Keyword(s):  
Interaction Network ◽  
Viral Proteins ◽  
Inhibitory Effect ◽  
Host Proteins ◽  
Disease Manifestation ◽  
Protein Protein Interaction ◽  
Human Proteins ◽  
Approved Drugs ◽  
Viral Lifecycle ◽  
Fda Approved Drugs

<p>The SARS-CoV2 is a highly contagious pathogen that causes a respiratory disease named COVID-19. The COVID-19 was declared a pandemic by the WHO on 11th March 2020. It has affected about 5.38 million people globally (identified cases as on 24th May 2020), with an average lethality of ~3%. Unfortunately, there is no standard cure for the disease, although some drugs are under clinical trial. Thus, there is an urgent need of drugs for the treatment of COVID-19. The molecularly targeted therapies have proven their utility in various diseases such as HIV, SARS, and HCV. Therefore, a lot of efforts are being directed towards the identification of molecules that can be helpful in the management of COVID-19. </p> <p>In the current studies, we have used state of the art bioinformatics techniques to screen the FDA approved drugs against thirteen SARS-CoV2 proteins in order to identify drugs for quick repurposing. The strategy was to identify potential drugs that can target multiple viral proteins simultaneously. Our strategy originates from the fact that individual viral proteins play specific role in multiple aspects of viral lifecycle such as attachment, entry, replication, morphogenesis and egress and targeting them simultaneously will have better inhibitory effect.</p> <p>Additionally, we analyzed if the identified molecules can also affect the host proteins whose expression is differentially modulated during SARS-CoV2 infection. The differentially expressed genes (DEGs) were identified using analysis of NCBI-GEO data (GEO-ID: GSE-147507). A pathway and protein-protein interaction network analysis of the identified DEGs led to the identification of network hubs that may play important roles in SARS-CoV2 infection. Therefore, targeting such genes may also be a beneficial strategy to curb disease manifestation. We have identified 29 molecules that can bind to various SARS-CoV2 and human host proteins. We hope that this study will help researchers in the identification and repurposing of multipotent drugs, simultaneously targeting the several viral and host proteins, for the treatment of COVID-19.</p>

scholarly journals Genomic analysis of human polymorphisms affecting drug-protein interactions

2017 ◽  
Author(s):  
Oriol Pich i Rosello ◽  
Anna V. Vlasova ◽  
Polina A. Shichkova ◽  
Yuri Markov ◽  
Peter K. Vlasov ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Protein Interactions ◽  
Low Frequency ◽  
Genomic Analysis ◽  
Binding Affinities ◽  
Using Data ◽  
Individual Drug Response ◽  
Approved Drugs ◽  
The Impact ◽  
Fda Approved Drugs

Human genetic variability is thought to account for a substantial fraction of individual biochemical characteristics – in biomedical sense, of individual drug response. However, only a handful of human genetic variants have been linked to medication outcomes. Here, we combine data on drug-protein interactions and human genome sequences to assess the impact of human variation on their binding affinity. Using data from the complexes of FDA-drugs and drug-like compounds, we predict SNPs substantially affecting the protein-ligand binding affinities. We estimate that an average individual carries ~6 SNPs affecting ~5 different FDA-approved drugs from among all of the approved compounds. SNPs affecting drug-protein binding affinity have low frequency in the population indicating that the genetic component for many ADEs may be highly personalized with each individual carrying a unique set of relevant SNPs. The reduction of ADEs, therefore, may primarily rely on the application of computational genome analysis in the clinic rather than the experimental study of common SNPs.

scholarly journals Ritonavir May Inhibit Exoribonuclease Activity of Nsp14 from the SARS-CoV-2 Virus and Potentiate the Activity of Chain Terminating Drugs

2020 ◽  
Author(s):  
naveen narayanan ◽  
deepak t nair
Keyword(s):  
Active Site ◽  
Genome Duplication ◽  
Protein A ◽  
Homology Model ◽  
Inhibitory Effect ◽  
Computational Studies ◽  
In Silico Screening ◽  
Therapeutic Properties ◽  
Approved Drugs ◽  
Fda Approved Drugs

<div>SARS-CoV-2 is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. The nsp14 protein of SARS-CoV-2 houses a 3’ to 5’ exoribonuclease activity responsible for removing mismatches that arise during genome duplication. A homology model of nsp10-nsp14 complex was used to carry out in silico screening to identify molecules among natural products, or FDA approved drugs that can potentially inhibit the activity of nsp14. This exercise showed that ritonavir might bind to the exoribonuclease active site of the nsp14 protein. A model of the SCV2-nsp10-nsp14 complex</div><div>bound to substrate RNA showed that the ritonavir binding site overlaps with that of the 3’ nucleotide of substrate RNA. A comparison of the calculated energies of binding for RNA and ritonavir suggested that the drug may bind to the active site of nsp14 with significant affinity. It is, therefore, possible that ritonavir may prevent association with substrate RNA and thus inhibit the exoribonuclease activity of nsp14. Overall, our computational studies suggest that ritonavir</div><div>may serve as an effective inhibitor of the nsp14 protein. nsp14 is known to attenuate the inhibitory effect of drugs that function through premature termination of viral genome</div><div>replication. Hence, ritonavir may potentiate the therapeutic properties of drugs such as remdesivir, favipiravir and ribavirin.</div>

scholarly journals Ritonavir may inhibit exoribonuclease activity of nsp14 from the SARS-CoV-2 virus and potentiate the activity of chain terminating drugs

2020 ◽  
Author(s):  
naveen narayanan ◽  
deepak t nair
Keyword(s):  
Active Site ◽  
Protein A ◽  
Homology Model ◽  
Inhibitory Effect ◽  
Genome Replication ◽  
In Silico Screening ◽  
Viral Genome Replication ◽  
Therapeutic Properties ◽  
Approved Drugs ◽  
Fda Approved Drugs

SARS-CoV-2 is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. The nsp14 protein of SARS-CoV-2 houses a 3’ to 5’exoribonuclease activity responsible for removing mismatches that arise during genome duplication. A homology model of nsp10-nsp14 complex was used to carry out in silico screening to identify molecules among natural products, or FDA approved drugs that can potentially inhibit the activity of nsp14. This exercise showed that ritonavir might bind to the exoribonuclease active site of the nsp14 protein. A model of the SCV2-nsp10-nsp14 complex bound to substrate RNA showed that the ritonavir binding site overlaps with that of the 3’nucleotide of substrate RNA. A comparison of the calculated energies of binding for RNA and ritonavir suggested that the drug may bind to the active site of nsp14 with significant affinity. It is, therefore, possible that ritonavir may prevent association with substrate RNA and thus inhibit the exoribonuclease activity of nsp14. Overall, our computational studies suggest that ritonavirmay serve as an effective inhibitor of the nsp14 protein. nsp14 is known to attenuate the inhibitory effect of drugs that function through premature termination of viral genome replication. Hence, ritonavir may potentiate the therapeutic properties of drugs such as remdesivir, favipiravir and ribavirin.

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