In-silico Structure-Based Drug Discovery of Candidate Drugs against Novel Protein Receptor Complex Nsp10-Nsp16 of SARS-CoV-2 using Drug Repurposing Approach

Coronaviruses ◽  
2020 ◽  
Vol 01 ◽  
Author(s):  
Abhishek Sengupta ◽  
Pooja Vijayaraghavan ◽  
Priyansh Srivastava ◽  
Lovely Gupta ◽  
Chaitanya Chandwani ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Drug Repurposing ◽  
Antiviral Drugs ◽  
Receptor Complex ◽  
Tanimoto Similarity ◽  
Protein Receptor ◽  
Complex Protein ◽  
Positive Results ◽  
Novel Protein

Background: Several therapeutic possibilities have been explored against Severe Acute Respiratory Syndrome-2 (SARS-CoV-2), such as convalescent plasma (CP), intravenous immunoglobulin (IVIG) and monoclonal antibodies. Compounds such as hydroxychloroquine have also been found to have fatal drawbacks. Repurposing of existing antiviral drugs can be an effective strategy, which could fasten up the process of drug discovery. Objective: The present study is designed to predict the computational efficacy of pre-existing antiviral drugs as inhibitors for the Nsp10-Nsp16 complex protein of SARS-CoV-2. Method: Twenty-six known antiviral drugs along with their similar structures based on Tanimoto similarity were screened towards Nsp10-Nsp16 complex’s active site. Result: Our study reports competitive binding of 1-[3-[2-(2-Ethoxyphenoxy) ethylamino]-2-hydroxypropyl] -9H-carbazol-4- ol against AdoMet binding site in Nsp10-Nsp16 complex. Formation of the stable ligand-receptor complex with 1-[3-[2-(2- Ethoxyphenoxy) ethylamino]-2-hydroxypropyl] -9H-carbazol-4-ol could functionally inhibit the Nsp10-Nsp16 complex, thereby making the SARS-CoV-2 vulnerable to host immuno-surveillance mechanisms. Conclusion: We conclude that these computational hits can display positive results in in-vitro trials against SARS-CoV-2.

Drug Discovery by Drug Repurposing: Combating COVID-19 in the 21st Century

2020 ◽  
Vol 20 ◽  
Author(s):  
Nitesh Sanghai ◽  
Kashfia Shafiq ◽  
Geoffrey K. Tranmer
Keyword(s):  
Drug Discovery ◽  
Drug Repurposing ◽  
Compassionate Use ◽  
Drug Candidates ◽  
Working Day ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Day By Day ◽  
Potential Use

: Due to the rapidly developing nature of the current COVID-19 outbreak and its almost immediate humanitarian and economic toll, coronavirus drug discovery efforts have largely focused on generating potential COVID-19 drug candidates as quickly as possible. Globally, scientists are working day and night to find the best possible solution to treat the deadly virus. During the first few months of 2020, the SARS-CoV-2 outbreak quickly developed into a pandemic, with a mortality rate that was increasing at an exponential rate day by day. As a result, scientists have turned to a drug repurposing approach, to rediscover the potential use and benefits of existing approved drugs. Currently, there is no single drug approved by the U.S. Food and Drug Administration (FDA), for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously known as 2019-nCoV) that causes COVID-19. Based on only in-vitro studies, several active drugs are already in the clinical pipeline, made possible by following the compassionate use of medicine protocols. This method of repurposing and the use of existing molecules like Remdesivir (GS-5734), Chloroquine, Hydroxychloroquine, etc. has proven to be a landmark in the field of drug rediscovery. In this review article we will discuss the repurposing of medicines for treating the deadly novel coronavirus (SARS-CoV-2).

scholarly journals Causal network models of SARS-CoV-2 expression and aging to identify candidates for drug repurposing

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Anastasiya Belyaeva ◽  
Louis Cammarata ◽  
Adityanarayanan Radhakrishnan ◽  
Chandler Squires ◽  
Karren Dai Yang ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Tyrosine Kinases ◽  
Large Scale ◽  
Drug Repurposing ◽  
Network Models ◽  
Structural Data ◽  
Multiple Data ◽  
Approved Drugs ◽  
Causal Framework

AbstractGiven the severity of the SARS-CoV-2 pandemic, a major challenge is to rapidly repurpose existing approved drugs for clinical interventions. While a number of data-driven and experimental approaches have been suggested in the context of drug repurposing, a platform that systematically integrates available transcriptomic, proteomic and structural data is missing. More importantly, given that SARS-CoV-2 pathogenicity is highly age-dependent, it is critical to integrate aging signatures into drug discovery platforms. We here take advantage of large-scale transcriptional drug screens combined with RNA-seq data of the lung epithelium with SARS-CoV-2 infection as well as the aging lung. To identify robust druggable protein targets, we propose a principled causal framework that makes use of multiple data modalities. Our analysis highlights the importance of serine/threonine and tyrosine kinases as potential targets that intersect the SARS-CoV-2 and aging pathways. By integrating transcriptomic, proteomic and structural data that is available for many diseases, our drug discovery platform is broadly applicable. Rigorous in vitro experiments as well as clinical trials are needed to validate the identified candidate drugs.

scholarly journals SARS-CoV-2 tropism, entry, replication, and propagation: Considerations for drug discovery and development

2021 ◽  
Vol 17 (2) ◽  
pp. e1009225
Author(s):  
Nicholas Murgolo ◽  
Alex G. Therien ◽  
Bonnie Howell ◽  
Daniel Klein ◽  
Kenneth Koeplinger ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Wide Spectrum ◽  
Drug Repurposing ◽  
Cellular Interactions ◽  
Severe Respiratory Distress ◽  
Initial Report ◽  
Future Drug ◽  
Immortalized Cell ◽  
Novel Coronavirus

Since the initial report of the novel Coronavirus Disease 2019 (COVID-19) emanating from Wuhan, China, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spread globally. While the effects of SARS-CoV-2 infection are not completely understood, there appears to be a wide spectrum of disease ranging from mild symptoms to severe respiratory distress, hospitalization, and mortality. There are no Food and Drug Administration (FDA)-approved treatments for COVID-19 aside from remdesivir; early efforts to identify efficacious therapeutics for COVID-19 have mainly focused on drug repurposing screens to identify compounds with antiviral activity against SARS-CoV-2 in cellular infection systems. These screens have yielded intriguing hits, but the use of nonhuman immortalized cell lines derived from non-pulmonary or gastrointestinal origins poses any number of questions in predicting the physiological and pathological relevance of these potential interventions. While our knowledge of this novel virus continues to evolve, our current understanding of the key molecular and cellular interactions involved in SARS-CoV-2 infection is discussed in order to provide a framework for developing the most appropriate in vitro toolbox to support current and future drug discovery efforts.

scholarly journals Machine Learning Models Identify Inhibitors of SARS-CoV-2

2020 ◽  
Author(s):  
Victor O. Gawriljuk ◽  
Phyo Phyo Kyaw Zin ◽  
Daniel H. Foil ◽  
Jean Bernatchez ◽  
Sungjun Beck ◽  
...  
Keyword(s):  
Machine Learning ◽  
Drug Discovery ◽  
Antiviral Drug ◽  
Drug Repurposing ◽  
Published Data ◽  
Learning Models ◽  
Machine Learning Model ◽  
Bayesian Machine Learning ◽  
Machine Learning Models

AbstractWith the ongoing SARS-CoV-2 pandemic there is an urgent need for the discovery of a treatment for the coronavirus disease (COVID-19). Drug repurposing is one of the most rapid strategies for addressing this need and numerous compounds have been selected for in vitro testing by several groups already. These have led to a growing database of molecules with in vitro activity against the virus. Machine learning models can assist drug discovery through prediction of the best compounds based on previously published data. Herein we have implemented several machine learning methods to develop predictive models from recent SARS-CoV-2 in vitro inhibition data and used them to prioritize additional FDA approved compounds for in vitro testing selected from our in-house compound library. From the compounds predicted with a Bayesian machine learning model, CPI1062 and CPI1155 showed antiviral activity in HeLa-ACE2 cell-based assays and represent potential repurposing opportunities for COVID-19. This approach can be greatly expanded to exhaustively virtually screen available molecules with predicted activity against this virus as well as a prioritization tool for SARS-CoV-2 antiviral drug discovery programs. The very latest model for SARS-CoV-2 is available at www.assaycentral.org.

scholarly journals Evaluation of Drug Repositioning by Molecular Docking of Pharmaceutical Resources to Identification of Potential SARS-CoV-2 Viral Inhibitors

2022 ◽  
Author(s):  
Fatemeh Hosseini ◽  
Mehrdad Azin ◽  
Hamideh Ofoghi ◽  
Tahereh Alinejad
Keyword(s):  
Molecular Docking ◽  
Drug Discovery ◽  
In Silico ◽  
De Novo ◽  
Drug Repositioning ◽  
Antiviral Drug ◽  
Drug Repurposing ◽  
Future Perspective

Unfortunately, to date, there is no approved specific antiviral drug treatment against COVID-19. Due to the costly and time-consuming nature of the de novo drug discovery and development process, in recent days, the computational drug repositioning method has been highly regarded for accelerating the drug-discovery process. The selection of drug target molecule(s), preparation of an approved therapeutics agent library, and in silico evaluation of their affinity to the subjected target(s) are the main steps of a molecular docking-based drug repositioning process, which is the most common computational drug re-tasking process. In this chapter, after a review on origin, pathophysiology, molecular biology, and drug development strategies against COVID-19, recent advances, challenges as well as the future perspective of molecular docking-based drug repositioning for COVID-19 are discussed. Furthermore, as a case study, the molecular docking-based drug repurposing process was planned to screen the 3CLpro inhibitor(s) among the nine Food and Drug Administration (FDA)-approved antiviral protease inhibitors. The results demonstrated that Fosamprenavir had the highest binding affinity to 3CLpro and can be considered for more in silico, in vitro, and in vivo evaluations as an effective repurposed anti-COVID-19 drug.

scholarly journals Bioactive Molecules of Tea as Potential Inhibitors for RNA-Dependent RNA Polymerase of SARS-CoV-2

2021 ◽  
Vol 8 ◽  
Author(s):  
Vijay Kumar Bhardwaj ◽  
Rahul Singh ◽  
Jatin Sharma ◽  
Vidya Rajendran ◽  
Rituraj Purohit ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Drug Repurposing ◽  
Docking Studies ◽  
Antiviral Drugs ◽  
Bioactive Molecules ◽  
Rna Dependent Rna Polymerase ◽  
Dynamics Simulations ◽  
Potential Inhibitors

The coronavirus disease (COVID-19), a worldwide pandemic, is caused by the severe acute respiratory syndrome-corona virus-2 (SARS-CoV-2). At this moment in time, there are no specific therapeutics available to combat COVID-19. Drug repurposing and identification of naturally available bioactive molecules to target SARS-CoV-2 are among the key strategies to tackle the notorious virus. The enzyme RNA-dependent RNA polymerase (RdRp) performs a pivotal role in replicating the virus. RdRp is a prime target for Remdesivir and other nucleotides analog-based antiviral drugs. In this study, we showed three bioactive molecules from tea (epicatechin-3,5-di-O-gallate, epigallocatechin-3,5-di-O-gallate, and epigallocatechin-3,4-di-O-gallate) that showed better interaction with critical residues present at the catalytic center and the NTP entry channel of RdRp than antiviral drugs Remdesivir and Favipiravir. Our computational approach to identify these molecules included molecular docking studies, followed by robust molecular dynamics simulations. All the three molecules are readily available in tea and could be made accessible along with other medications to treat COVID-19 patients. However, these results require validation by further in vitro and in vivo studies.

Sitagliptin: a potential drug for the treatment of SARS-CoV-2?

2020 ◽  
Author(s):  
Sanaa Bardaweel
Keyword(s):  
Clinical Trials ◽  
Drug Discovery ◽  
Antimalarial Drug ◽  
Drug Repurposing ◽  
Spike Protein ◽  
Diabetic Patients ◽  
Potential Drug ◽  
Chemokine Production ◽  
Drug Discovery And Development ◽  
Sequence Identity

Recently, an outbreak of fatal coronavirus, SARS-CoV-2, has emerged from China and is rapidly spreading worldwide. As the coronavirus pandemic rages, drug discovery and development become even more challenging. Drug repurposing of the antimalarial drug chloroquine and its hydroxylated form had demonstrated apparent effectiveness in the treatment of COVID-19 associated pneumonia in clinical trials. SARS-CoV-2 spike protein shares 31.9% sequence identity with the spike protein presents in the Middle East Respiratory Syndrome Corona Virus (MERS-CoV), which infects cells through the interaction of its spike protein with the DPP4 receptor found on macrophages. Sitagliptin, a DPP4 inhibitor, that is known for its antidiabetic, immunoregulatory, anti-inflammatory, and beneficial cardiometabolic effects has been shown to reverse macrophage responses in MERS-CoV infection and reduce CXCL10 chemokine production in AIDS patients. We suggest that Sitagliptin may be beneficial alternative for the treatment of COVID-19 disease especially in diabetic patients and patients with preexisting cardiovascular conditions who are already at higher risk of COVID-19 infection.

Sign in / Sign up

Export Citation Format

Share Document