Computational drug repurposing for the identification of SARS-CoV-2 main protease inhibitors.

J Biomol Struct Dyn. 2020 Jul 24;:1-7

Authors: Fiorucci D, Milletti E, Orofino F, Brizzi A, Mugnaini C, Corelli F

Abstract
Accepted 7 July 2020ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the known COVID-19 disease. Since currently no definitive therapies or vaccines for the SARS-CoV-2 virus are available, there is an urgent need to identify effective drugs against SARS-CoV-2 infection. One of the best-known targets available is the main protease of this virus, crucial for the processing of polyproteins codified by viral RNA. In this work, we used a computational virtual screening procedure for the repurposing of commercial drugs available in the DrugBank database as inhibitors of the SARS-CoV-2 main protease. Molecular docking calculations and molecular dynamics (MD) simulations have been applied. The computational model was validated through a self-docking procedure. The screening procedure highlighted five interesting drugs that showed a comparable or higher docking score compared to the crystallographic compound and maintained the protein binding during the MD runs. Amongst these drugs, Ritonavir has been used in clinical trials with patients affected by COVID-19 and Nelfinavir showed anti-SARS-CoV-2 activity. The five identified drugs could be evaluated experimentally as inhibitors of the SARS-CoV-2 main protease in view of a possible COVID-19 treatment. Communicated by Ramaswamy H. Sarma.

PMID: 32705942 [PubMed - as supplied by publisher]

Drug-target interactions prediction using marginalized denoising model on heterogeneous networks.

BMC Bioinformatics. 2020 Jul 23;21(1):330

Authors: Tang C, Zhong C, Chen D, Wang J

Abstract
BACKGROUND: Drugs achieve pharmacological functions by acting on target proteins. Identifying interactions between drugs and target proteins is an essential task in old drug repositioning and new drug discovery. To recommend new drug candidates and reposition existing drugs, computational approaches are commonly adopted. Compared with the wet-lab experiments, the computational approaches have lower cost for drug discovery and provides effective guidance in the subsequent experimental verification. How to integrate different types of biological data and handle the sparsity of drug-target interaction data are still great challenges.
RESULTS: In this paper, we propose a novel drug-target interactions (DTIs) prediction method incorporating marginalized denoising model on heterogeneous networks with association index kernel matrix and latent global association. The experimental results on benchmark datasets and new compiled datasets indicate that compared to other existing methods, our method achieves higher scores of AUC (area under curve of receiver operating characteristic) and larger values of AUPR (area under precision-recall curve).
CONCLUSIONS: The performance improvement in our method depends on the association index kernel matrix and the latent global association. The association index kernel matrix calculates the sharing relationship between drugs and targets. The latent global associations address the false positive issue caused by network link sparsity. Our method can provide a useful approach to recommend new drug candidates and reposition existing drugs.

PMID: 32703151 [PubMed - in process]

[The naked king in the pandemic: about the production and communication of scientific knowledge at the time of SARS-CoV-2.]

Recenti Prog Med. 2020 Jul-Aug;111(7):398-401

Authors: Alderighi C, Rasoini R

Abstract
The SARS-CoV-2 pandemic has lifted the veil about how medical knowledge is produced and disseminated. Action Bias, together with economic, academic and media-related interests, has concurred to generate and spread low-value and even unreliable information about some hypothetical therapeutic interventions for CoViD-19. Not only this "infodemic" has weakened people's ability to make informed health choices, but it also has influenced the process of new evidence generation through the violation of the equipoise principle. The CoViD-19 infodemic has further highlighted the need for reliable health information and for people to enter the process of understanding and promoting valuable research. Through a randomized controlled trial, the Informed Health Choices project has shown that it is not impossible neither quixotic to better orient people about health choices since primary school. Similar competencies should be disseminated to everyone through sources that are selected and validated for their capability of reporting evidence based health information about the effects of treatments.

PMID: 32658877 [PubMed - indexed for MEDLINE]

How Genes Move: Spatial Repositioning of Activated Genes Is Driven by Nuclear Actin-Based Pathway.

Dev Cell. 2020 02 10;52(3):252-254

Authors: Capelson M

Abstract
Spatial repositioning of genes in nuclear space has been extensively linked to regulation of gene expression, but the mechanisms behind this directed movement have remained uncertain. In this issue of Developmental Cell, Wang et al. (2020) describe a nuclear actin-myosin-based pathway driving the movement of activated genes to the nuclear periphery.

PMID: 32049034 [PubMed - indexed for MEDLINE]

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2020/07/24

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Potentially repurposable drugs for COVID-19 identified from SARS-CoV-2 Host Protein Interactome.

Res Sq. 2020 May 28;:

Authors: Karunakaran KB, Balakrishnan N, Ganapathiraju M

Abstract
We previously presented the protein-protein interaction network - the 'HoP' or the host protein interactome - of 332 host proteins that were identified to interact with 27 nCoV19 viral proteins by Gordon et al. Here, we studied drugs targeting the proteins in this interactome to identify whether any of them may potentially be repurposable against SARS-CoV-2. We studied each of the drugs using the BaseSpace Correlation Engine and identified those that induce gene expression profiles negatively correlated with SARS-associated expression profile. This analysis resulted in 20 drugs whose differential gene expression (drug versus normal) had an anti-correlation with differential expression for SARS (viral infection versus normal). These included drugs that were already being tested for their clinical activity against SARS-CoV-2, those with proven activity against SARS-CoV/MERS-CoV, broad-spectrum antiviral drugs, and those identified/prioritized by other computational re-purposing studies. In summary, our integrated computational analysis of the HoP interactome in conjunction with drug-induced transcriptomic data resulted in drugs that may be repurposable for COVID-19.

PMID: 32702734 [PubMed - as supplied by publisher]

In silico Drug Repurposing to combat COVID-19 based on Pharmacogenomics of Patient Transcriptomic Data.

Res Sq. 2020 Jun 30;:

Authors: Das S, Camphausen K, Shankavaram U

Abstract
The ongoing global pandemic of coronavirus disease 2019 (COVID-19) continues to affect a growing number of populations in different parts of the world. In the current situation, drug repurposing is a viable strategy to combat COVID-19. The drugs targeting the host receptors that interact with SARS-CoV-2 are possible candidates. However, assessment of their effectiveness in COVID-19 patients is necessary before prioritizing them for further study. We attempted to shortlist the candidate drugs using an in-silico approach. First, we analysed two published transcriptomic data sets of COVID-19- and SARS-infected patients compared to healthy individuals to find the key pathways altered after infection. Then, using publicly available drug perturbational data sets in human cell lines from the Broad Institute Connectivity Map (CMAP), we assessed the effects of the approved drugs on the altered pathways. We also used the available pharmacogenomic data sets from the Genomics of Drug Sensitivity in Cancer (GDSC) portal to assess the effects of the altered pathways on resistance or sensitivity to the drugs in human cell lines. Our analysis identified many candidate drugs, some of which are already being investigated for treatment of COVID-19 and can serve as a basis for prioritizing additional viable candidate drugs for COVID-19.

PMID: 32702730 [PubMed - as supplied by publisher]

Recent advances in sarcoidosis genomics: epigenetics, gene expression, and gene by environment (G × E) interaction studies.

Curr Opin Pulm Med. 2020 Jul 20;:

Authors: Garman L, Montgomery CG, Rivera NV

Abstract
PURPOSE OF REVIEW: We aim to review the most recent findings in genomics of sarcoidosis and highlight the gaps in the field.
RECENT FINDINGS: Original explorations of sarcoidosis subphenotypes, including cases associated with the World Trade Center and ocular sarcoidosis, have identified novel risk loci. Innovative gene--environment interaction studies utilizing modern analytical techniques have discovered risk loci associated with smoking and insecticide exposure. The application of whole-exome sequencing has identified genetic variants associated with persistent sarcoidosis and rare functional variations. A single epigenomics study has provided background knowledge of DNA methylation mechanisms in comparison with gene expression data. The application of machine-learning techniques has suggested new drug repositioning for the treatment of sarcoidosis. Several gene expression studies have identified prominent inflammatory pathways enriched in the affected tissue.
SUMMARY: Certainly, sarcoidosis research has recently advanced in the exploration of disease subphenotypes, utilizing novel analytical techniques, and including measures of clinical variation. Nevertheless, large-scale and diverse cohorts investigated with advanced sequencing methods, such as whole-genome and single-cell RNA sequencing, epigenomics, and meta-analysis coupled with cutting-edge analytic approaches, when employed, will broaden and translate genomics findings into clinical applications, and ultimately open venues for personalized medicine.

PMID: 32701681 [PubMed - as supplied by publisher]

Cepharanthine: a review of the antiviral potential of a Japanese-approved alopecia drug in COVID-19.

Pharmacol Rep. 2020 Jul 22;:

Authors: Rogosnitzky M, Okediji P, Koman I

Abstract
Cepharanthine (CEP) is a naturally occurring alkaloid derived from Stephania cepharantha Hayata and demonstrated to have unique anti-inflammatory, antioxidative, immunomodulating, antiparasitic, and antiviral properties. Its therapeutic potential as an antiviral agent has never been more important than in combating COVID-19 caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) virus. Cepharanthine suppresses nuclear factor-kappa B (NF-κB) activation, lipid peroxidation, nitric oxide (NO) production, cytokine production, and expression of cyclooxygenase; all of which are crucial to viral replication and inflammatory response. Against SARS-CoV-2 and homologous viruses, CEP predominantly inhibits viral entry and replication at low doses; and was recently identified as the most potent coronavirus inhibitor among 2406 clinically approved drug repurposing candidates in a preclinical model. This review critically analyzes and consolidates available evidence establishing CEP's potential therapeutic importance as a drug of choice in managing COVID-19 cases.

PMID: 32700247 [PubMed - as supplied by publisher]

Dual inhibitors of SARS-CoV-2 proteases: pharmacophore and molecular dynamics based drug repositioning and phytochemical leads.

J Biomol Struct Dyn. 2020 Jul 22;:1-14

Authors: Mitra K, Ghanta P, Acharya S, Chakrapani G, Ramaiah B, Doble M

Abstract
SARS-related coronaviruses poses continual threat to humanity by rapidly mutating and emerging as severe pandemic outbreaks, including the current nCoV-19 pandemic. Hence a rapid drug repositioning and lead identification strategy are required to mitigate these outbreaks. We report a pharmacophore and molecular dynamics-based approach for drug repositioning and lead identification against dual targets (3CLp and PLp) of SARS-CoV-2. The pharmacophore model of 3CLp inhibitors was apolar with two aromatic and two H-bond acceptors, whereas that of PLp was relatively polar, bearing one aromatic and three H-bond acceptors. Pharmacophore-based virtual screening yielded six existing FDA-approved drugs and twelve natural products with both the pharmacophoric features. Among them are nelfinavir, tipranavir and licochalcone-D, which has shown better binding characteristics with both the proteases compared to lopinavir. The molecular dynamics revealed that the connecting loop (residues 176-199) of 3CLp is highly flexible, and hence, inhibitors should avoid high-affinity interactions with it. Lopinavir, due to its high affinity with the loop region, exhibited unstable binding. Further, the van der Waals size of the 3CLp inhibitors positively correlated with their binding affinity with 3CLp. However, the van der Waals size of a ligand should not cross a threshold of 572Å3, beyond which the ligands are likely to make high-affinity interaction with the loop and suffer unstable binding as observed in the case of lopinavir. Similarly, the total polar surface area of the ligands were found to be negatively correlated with their binding affinity with PLp.

PMID: 32698693 [PubMed - as supplied by publisher]

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2020/07/23

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2020/07/22

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2020/07/22

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2020/07/21

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Safety perspectives on presently considered drugs for the treatment of COVID-19.

Br J Pharmacol. 2020 Jul 17;:

Authors: Penman SL, Kiy RT, Jensen RL, Beoku-Betts C, Alfirevic A, Back D, Khoo SH, Owen A, Pirmohamed M, Park BK, Meng X, Goldring CE, Chadwick AE

Abstract
Intense effort is underway to evaluate potential therapeutic agents for the treatment of COVID-19. In order to respond quickly to the crisis, the repurposing of existing drugs is the primary pharmacological strategy. Despite the urgent clinical need for these therapies, it is imperative to consider potential safety issues. This is important due to the harm-benefit ratios that may be encountered when treating COVID-19, which can depend on the stage of the disease, when therapy is administered and underlying clinical factors in individual patients. Treatments are currently being trialled for a range of scenarios from prophylaxis (where benefit must greatly exceed risk) to severe life-threatening disease (where a degree of potential risk may be tolerated if it is exceeded by the potential benefit). In this perspective, we have reviewed some of the most widely-researched repurposed agents in order to identify potential safety considerations using existing information in the context of COVID-19.

PMID: 32681537 [PubMed - as supplied by publisher]

Targeting EMT in Cancer with Repurposed Metabolic Inhibitors.

Trends Cancer. 2020 Jul 15;:

Authors: Ramesh V, Brabletz T, Ceppi P

Abstract
Epithelial-to-mesenchymal transition (EMT) determines the most lethal features of cancer, metastasis formation and chemoresistance, and therefore represents an attractive target in oncology. However, direct targeting of EMT effector molecules is, in most cases, pharmacologically challenging. Since emerging research has highlighted the distinct metabolic circuits involved in EMT, we propose the use of metabolism-specific inhibitors, FDA approved or under clinical trials, as a drug repurposing approach to target EMT in cancer. Metabolism-inhibiting drugs could be coupled with standard chemo- or immunotherapy to combat EMT-driven resistant and aggressive cancers.

PMID: 32680650 [PubMed - as supplied by publisher]

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2020/07/18

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Special issue: Drug Repurposing for Cancer Therapy.

Semin Cancer Biol. 2020 Jul 14;:

Authors: Srivastava SK

PMID: 32679189 [PubMed - as supplied by publisher]

Drug repurposing studies targeting SARS-CoV-2: an ensemble docking approach on drug target 3C-like protease (3CLpro).

J Biomol Struct Dyn. 2020 Jul 17;:1-21

Authors: Koulgi S, Jani V, Uppuladinne M, Sonavane U, Nath AK, Darbari H, Joshi R

Abstract
The COVID-19 pandemic has been responsible for several deaths worldwide. The causative agent behind this disease is the Severe Acute Respiratory Syndrome - novel Coronavirus 2 (SARS-CoV-2). SARS-CoV-2 belongs to the category of RNA viruses. The main protease, responsible for the cleavage of the viral polyprotein is considered as one of the hot targets for treating COVID-19. Earlier reports suggest the use of HIV anti-viral drugs for targeting the main protease of SARS-CoV, which caused SARS in the year 2002-2003. Hence, drug repurposing approach may prove to be useful in targeting the main protease of SARS-CoV-2. The high-resolution crystal structure of the main protease of SARS-CoV-2 (PDB ID: 6LU7) was used as the target. The Food and Drug Administration approved and SWEETLEAD database of drug molecules were screened. The apo form of the main protease was simulated for a cumulative of 150 ns and 10 μs open-source simulation data was used, to obtain conformations for ensemble docking. The representative structures for docking were selected using RMSD-based clustering and Markov State Modeling analysis. This ensemble docking approach for the main protease helped in exploring the conformational variation in the drug-binding site of the main protease leading to the efficient binding of more relevant drug molecules. The drugs obtained as top hits from the ensemble docking possessed anti-bacterial and anti-viral properties. This in silico ensemble docking approach would support the identification of potential candidates for repurposing against COVID-19. Communicated by Ramaswamy H. Sarma.

PMID: 32679006 [PubMed - as supplied by publisher]

Synthetic repurposing of drugs against hypertension: a datamining method based on association rules and a novel discrete algorithm.

BMC Bioinformatics. 2020 Jul 16;21(1):313

Authors: Masoudi-Sobhanzadeh Y, Masoudi-Nejad A

Abstract
BACKGROUND: Drug repurposing aims to detect the new therapeutic benefits of the existing drugs and reduce the spent time and cost of the drug development projects. The synthetic repurposing of drugs may prove to be more useful than the single repurposing in terms of reducing toxicity and enhancing efficacy. However, the researchers have not given it serious consideration. To address the issue, a novel datamining method is introduced and applied to repositioning of drugs for hypertension (HT) which is a serious medical condition and needs some improved treatment plans to help treat it.
RESULTS: A novel two-step data mining method, which is based on the If-Then association rules as well as a novel discrete optimization algorithm, was introduced and applied to the synthetic repurposing of drugs for HT. The required data were also extracted from DrugBank, KEGG, and DrugR+ databases. The findings indicated that based on the different statistical criteria, the proposed method outperformed the other state-of-the-art approaches. In contrast to the previously proposed methods which had failed to discover a list on some datasets, our method could find a combination list for all of them.
CONCLUSION: Since the proposed synthetic method uses medications in small dosages, it might revive some failed drug development projects and put forward a suitable plan for treating different diseases such as COVID-19 and HT. It is also worth noting that applying efficient computational methods helps to produce better results.

PMID: 32677879 [PubMed - as supplied by publisher]