scholarly journals Using systems medicine to identify a therapeutic agent with potential for repurposing in inflammatory bowel disease

2020 ◽  
Vol 13 (11) ◽  
pp. dmm044040 ◽  
Author(s):  
Katie Lloyd ◽  
Stamatia Papoutsopoulou ◽  
Emily Smith ◽  
Philip Stegmaier ◽  
Francois Bergey ◽  
...  
Keyword(s):  
Drug Discovery ◽  
In Silico ◽  
Nuclear Translocation ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
Peritoneal Macrophages ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Aseptic Conditions ◽  
Novel Drug

ABSTRACTInflammatory bowel diseases (IBDs) cause significant morbidity and mortality. Aberrant NF-κB signalling is strongly associated with these conditions, and several established drugs influence the NF-κB signalling network to exert their effect. This study aimed to identify drugs that alter NF-κB signalling and could be repositioned for use in IBD. The SysmedIBD Consortium established a novel drug-repurposing pipeline based on a combination of in silico drug discovery and biological assays targeted at demonstrating an impact on NF-κB signalling, and a murine model of IBD. The drug discovery algorithm identified several drugs already established in IBD, including corticosteroids. The highest-ranked drug was the macrolide antibiotic clarithromycin, which has previously been reported to have anti-inflammatory effects in aseptic conditions. The effects of clarithromycin effects were validated in several experiments: it influenced NF-κB-mediated transcription in murine peritoneal macrophages and intestinal enteroids; it suppressed NF-κB protein shuttling in murine reporter enteroids; it suppressed NF-κB (p65) DNA binding in the small intestine of mice exposed to lipopolysaccharide; and it reduced the severity of dextran sulphate sodium-induced colitis in C57BL/6 mice. Clarithromycin also suppressed NF-κB (p65) nuclear translocation in human intestinal enteroids. These findings demonstrate that in silico drug repositioning algorithms can viably be allied to laboratory validation assays in the context of IBD, and that further clinical assessment of clarithromycin in the management of IBD is required.This article has an associated First Person interview with the joint first authors of the paper.

scholarly journals Using systems medicine to identify a therapeutic agent with potential for repurposing in Inflammatory Bowel Disease

2019 ◽  
Author(s):  
Katie Lloyd ◽  
Stamatia Papoutsopoulou ◽  
Emily Smith ◽  
Philip Stegmaier ◽  
Francois Bergey ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Drug Discovery ◽  
Bowel Disease ◽  
In Silico ◽  
Nuclear Translocation ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
Peritoneal Macrophages ◽  
Inflammatory Bowel ◽  
Aseptic Conditions

AbstractObjectiveInflammatory bowel diseases cause significant morbidity and mortality. Aberrant NF-κB signalling is strongly associated with these conditions, and several established drugs influence the NF-κB signalling network to exert their effect. This study aimed to identify drugs which alter NF-κB signalling and may be repositioned for use in inflammatory bowel disease.DesignThe SysmedIBD consortium established a novel drug-repurposing pipeline based on a combination of in-silico drug discovery and biological assays targeted at demonstrating an impact on NF-kappaB signalling, and a murine model of IBD.ResultsThe drug discovery algorithm identified several drugs already established in IBD, including corticosteroids. The highest-ranked drug was the macrolide antibiotic Clarithromycin, which has previously been reported to have anti-inflammatory effects in aseptic conditions.Clarithromycin’s effects were validated in several experiments: it influenced NF-κB mediated transcription in murine peritoneal macrophages and intestinal enteroids; it suppressed NF-κB protein shuttling in murine reporter enteroids; it suppressed NF-κB (p65) DNA binding in the small intestine of mice exposed to LPS, and it reduced the severity of dextran sulphate sodium-induced colitis in C57BL/6 mice. Clarithromycin also suppressed NF-κB (p65) nuclear translocation in human intestinal enteroids.ConclusionsThese findings demonstrate that in-silico drug repositioning algorithms can viably be allied to laboratory validation assays in the context of inflammatory bowel disease; and that further clinical assessment of clarithromycin in the management of inflammatory bowel disease is required.

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.

Recent Advances in Drug Repurposing for Parkinson’s Disease

2019 ◽  
Vol 26 (28) ◽  
pp. 5340-5362 ◽  
Author(s):  
Xin Chen ◽  
Giuseppe Gumina ◽  
Kristopher G. Virga
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drug Discovery ◽  
De Novo ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
Cost Effective ◽  
New Drugs ◽  
Recent Advances ◽  
Clinical Drugs

:As a long-term degenerative disorder of the central nervous system that mostly affects older people, Parkinson’s disease is a growing health threat to our ever-aging population. Despite remarkable advances in our understanding of this disease, all therapeutics currently available only act to improve symptoms but cannot stop the disease progression. Therefore, it is essential that more effective drug discovery methods and approaches are developed, validated, and used for the discovery of disease-modifying treatments for Parkinson’s disease. Drug repurposing, also known as drug repositioning, or the process of finding new uses for existing or abandoned pharmaceuticals, has been recognized as a cost-effective and timeefficient way to develop new drugs, being equally promising as de novo drug discovery in the field of neurodegeneration and, more specifically for Parkinson’s disease. The availability of several established libraries of clinical drugs and fast evolvement in disease biology, genomics and bioinformatics has stimulated the momentums of both in silico and activity-based drug repurposing. With the successful clinical introduction of several repurposed drugs for Parkinson’s disease, drug repurposing has now become a robust alternative approach to the discovery and development of novel drugs for this disease. In this review, recent advances in drug repurposing for Parkinson’s disease will be discussed.

scholarly journals An integrated dataset for in silico drug discovery

2010 ◽  
Vol 7 (3) ◽  
Author(s):  
Simon J Cockell ◽  
Jochen Weile ◽  
Phillip Lord ◽  
Claire Wipat ◽  
Dmytro Andriychenko ◽  
...  
Keyword(s):  
Systems Biology ◽  
Drug Discovery ◽  
Drug Development ◽  
Data Integration ◽  
In Silico ◽  
Drug Repositioning ◽  
Integrated Systems ◽  
Integration Platform ◽  
Treatment Indications ◽  
New Treatment

SummaryDrug development is expensive and prone to failure. It is potentially much less risky and expensive to reuse a drug developed for one condition for treating a second disease, than it is to develop an entirely new compound. Systematic approaches to drug repositioning are needed to increase throughput and find candidates more reliably. Here we address this need with an integrated systems biology dataset, developed using the Ondex data integration platform, for the in silico discovery of new drug repositioning candidates. We demonstrate that the information in this dataset allows known repositioning examples to be discovered. We also propose a means of automating the search for new treatment indications of existing compounds.

scholarly journals Stiffness Regulates Intestinal Stem Cell Fate

2021 ◽  
Author(s):  
Shijie He ◽  
Peng Lei ◽  
Wenying Kang ◽  
Priscilla Cheung ◽  
Tao Xu ◽  
...  
Keyword(s):  
Cell Fate ◽  
Nuclear Translocation ◽  
Goblet Cells ◽  
Metabolic Phenotype ◽  
Hydrogel Matrix ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
The Impact

SummaryDoes fibrotic gut stiffening caused by inflammatory bowel diseases (IBD) direct the fate of intestinal stem cells (ISCs)? To address this question we first developed a novel long-term culture of quasi-3D gut organoids plated on hydrogel matrix of varying stiffness. Stiffening from 0.6kPa to 9.6kPa significantly reduces Lgr5high ISCs and Ki67+ progenitor cells while promoting their differentiation towards goblet cells. These stiffness-driven events are attributable to YAP nuclear translocation. Matrix stiffening also extends the expression of the stemness marker Olfactomedin 4 (Olfm4) into villus-like regions, mediated by cytoplasmic YAP. We next used single-cell RNA sequencing to generate for the first time the stiffness-regulated transcriptional signatures of ISCs and their differentiated counterparts. These signatures confirm the impact of stiffening on ISC fate and additionally suggest a stiffening-induced switch in metabolic phenotype, from oxidative phosphorylation to glycolysis. Finally, we used colon samples from IBD patients as well as chronic colitis murine models to confirm the in vivo stiffening-induced epithelial deterioration similar to that observed in vitro. Together, these results demonstrate stiffness-dependent ISC reprograming wherein YAP nuclear translocation diminishes ISCs and Ki67+ progenitors and drives their differentiation towards goblet cells, suggesting stiffening as potential target to mitigate gut epithelial deterioration during IBD.

scholarly journals A review on drug repurposing applicable to COVID-19

2020 ◽  
Author(s):  
Serena Dotolo ◽  
Anna Marabotti ◽  
Angelo Facchiano ◽  
Roberto Tagliaferri
Keyword(s):  
Artificial Intelligence ◽  
Drug Target ◽  
Lower Cost ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
Chemical Compounds ◽  
The Moment ◽  
New Applications ◽  
Novel Drug ◽  
Small Chemical

Abstract Drug repurposing involves the identification of new applications for existing drugs at a lower cost and in a shorter time. There are different computational drug-repurposing strategies and some of these approaches have been applied to the coronavirus disease 2019 (COVID-19) pandemic. Computational drug-repositioning approaches applied to COVID-19 can be broadly categorized into (i) network-based models, (ii) structure-based approaches and (iii) artificial intelligence (AI) approaches. Network-based approaches are divided into two categories: network-based clustering approaches and network-based propagation approaches. Both of them allowed to annotate some important patterns, to identify proteins that are functionally associated with COVID-19 and to discover novel drug–disease or drug–target relationships useful for new therapies. Structure-based approaches allowed to identify small chemical compounds able to bind macromolecular targets to evaluate how a chemical compound can interact with the biological counterpart, trying to find new applications for existing drugs. AI-based networks appear, at the moment, less relevant since they need more data for their application.

scholarly journals In Silico Drug Repositioning Against Human NRP1 to Block SARS-CoV-2 Host Entry

2020 ◽  
Author(s):  
Seref Gul
Keyword(s):  
Drug Discovery ◽  
In Silico ◽  
Structural Information ◽  
Drug Repositioning ◽  
Experimental Studies ◽  
Md Simulations ◽  
Drug Binding ◽  
Discovery Process ◽  
Drug Discovery Process ◽  
S Protein

Despite COVID-19 turned into a pandemic, no approved drug for the treatment or globally available vaccine is out yet. In such a global emergency, drug repurposing approach that bypasses a costly and long-time demanding drug discovery process is an effective way in search of finding drugs for the COVID-19 treatment. Recent studies showed that SARS-CoV-2 uses neuropilin-1 (NRP1) for host entry. Here I took advantage of structural information of the NRP1 in complex with C-terminal of spike (S) protein of SARS-CoV-2 to identify drugs that may inhibit NRP1 and S protein interaction. U.S. Food and Drug Administration (FDA) approved drugs were screened using docking simulations. Among top drugs, well-tolerated drugs were selected for further analysis. Molecular dynamics (MD) simulations of drugs-NRP1 complexes were run for 100 ns to assess the persistency of binding. MM/GBSA calculations from MD simulations showed that eltrombopag, glimepiride, sitagliptin, dutasteride, and ergotamine stably and strongly bind to NRP1. In silico Alanine scanning analysis revealed that Tyr<sup>297</sup>, Trp<sup>301</sup>, and Tyr<sup>353</sup> amino acids of NRP1 are critical for drug binding. Validating the effect of drugs analyzed in this paper by experimental studies and clinical trials will expedite the drug discovery process for COVID-19.

scholarly journals Shotgun Drug Repurposing Biotechnology to Tackle Epidemics and Pandemics

2020 ◽  
Author(s):  
William Mangione ◽  
Zackary Falls ◽  
Thomas Melendy ◽  
Gaurav Chopra ◽  
Ram Samudrala
Keyword(s):  
Clinical Trials ◽  
Drug Discovery ◽  
Computational Analysis ◽  
Drug Repurposing ◽  
The Future ◽  
Respiratory Coronavirus ◽  
Novel Drug

In this manuscript we highlight consensus between the list of drugs currently in clinical trials to treat COVID-19, the worldwide pandemic caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), and the list of predictions made using our shotgun drug discovery, repurposing, and design platform known as CANDO (Computational Analysis of Novel Drug Opportunities). We make the argument that increased funding and development for drug repurposing biotechnology like ours will help combat the inevitable pathogenic outbreaks of the future. <br>

scholarly journals Anti Hepatitis C virus drugs show potential drug repositioning for SARS CoV-2 main protease: an in silico study

2020 ◽  
Author(s):  
Arthikasree Anandamurthy ◽  
Roslin Elsa Varughese ◽  
Saranya Sivaraj ◽  
Gayathri Dasararaju
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
In Silico ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
Docking Study ◽  
Binding Potential ◽  
Molecular Docking Study ◽  
Main Protease ◽  
Potent Drug

Abstract Developing effective and safe vaccines/drugs against SARS CoV-2 may take some time. The urgency of the outbreak has led to the usage of broad spectrum of existing anti-viral drugs, across the globe. Among the existing anti-viral drugs, there is still a challenge in identifying the potent drug or the combination of the drugs for the better treatment and faster recovery of the patients. In silico molecular docking study aids in the process of drug repurposing and we aimed to identify the binding potential of some of the existing anti-viral drugs and their interactions at the active site of SARS CoV-2 main protease. Results from our study revealed that the drugs Simeprevir, Elbasvir, Paritaprevir, Beclabuvir, Dasabuvir, Teleprevir, Velpatasvir, Ombitasvir, Ledipasvir, Boceprevir, Asunapervir, Declatasvir, Sofusbuvir which are used in the treatment of Hepatitis C virus infection may act as potent inhibitors for SARS CoV-2 main protease.

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