Drug repositioning by merging active subnetworks validated in cancer and COVID-19

AbstractComputational drug repositioning aims at ranking and selecting existing drugs for novel diseases or novel use in old diseases. In silico drug screening has the potential for speeding up considerably the shortlisting of promising candidates in response to outbreaks of diseases such as COVID-19 for which no satisfactory cure has yet been found. We describe DrugMerge as a methodology for preclinical computational drug repositioning based on merging multiple drug rankings obtained with an ensemble of disease active subnetworks. DrugMerge uses differential transcriptomic data on drugs and diseases in the context of a large gene co-expression network. Experiments with four benchmark diseases demonstrate that our method detects in first position drugs in clinical use for the specified disease, in all four cases. Application of DrugMerge to COVID-19 found rankings with many drugs currently in clinical trials for COVID-19 in top positions, thus showing that DrugMerge can mimic human expert judgment.

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Drug Repositioning by Merging Active Subnetworks Validated in Cancer and COVID-19

10.1101/2021.05.13.21257140 ◽

2021 ◽

Author(s):

Marta Lucchetta ◽

MARCO Pellegrini

Keyword(s):

State Of The Art ◽

Drug Repositioning ◽

Multiple Drug ◽

Digital Form ◽

Connectivity Map ◽

In Silico Screening ◽

Transcriptomic Data ◽

Large Gene ◽

Construction Algorithms ◽

Omic Data

Computational Drug Repositioning aims at ranking and selecting existing drugs for use in novel diseases or existing diseases for which these drugs were not originally designed. Using vast amounts of available omic data in digital form within an in silico screening has the potential for speeding up considerably the shortlisting of promising candidates in response to outbreaks of diseases such as COVID-19 for which no satisfactory cure has yet been found. We describe DrugMerge as a methodology for preclinical computational drug repositioning based on merging multiple drug rankings obtained with an ensemble of Disease Active Subnetwork construction algorithms. DrugMerge uses differential transcriptomic data from cell lines/tissues of patients affected by the disease and differential transcriptomic data from drug perturbation assays, in the context of a large gene co-expression network. Experiments with four benchmark diseases (Asthma, Rheumatoid Arthritis, Prostate Cancer, and Colorectal Cancer) demonstrate that our method detects in first position drugs in clinical use for the specified disease, in all four cases. Our method is competitive with the state-of-the-art tools such as CMAP (Connectivity Map). Application of DrugMerge to COVID-19 data found rankings with many drugs currently in clinical trials for COVID-19 in top positions, thus showing that DrugMerge is able to mimic human expert judgment

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Exploring the Power and the Promise of In Silico Clinical Trials: Possible Applications in COVID-19 Pandemic

SSRN Electronic Journal ◽

10.2139/ssrn.3638283 ◽

2020 ◽

Author(s):

Abdelrahman H. Abdelmoneim ◽

Safinaz I. Khalil ◽

Hiba A. Osman ◽

Ayesan Rewane ◽

Sahar G. Elbage

Keyword(s):

Clinical Trials ◽

In Silico

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In silico imaging clinical trials: cheaper, faster, better, safer, and more scalable

Trials ◽

10.1186/s13063-020-05002-w ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Aldo Badano

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Medical Devices ◽

In Silico ◽

Lessons Learned ◽

Patient Access ◽

High Quality ◽

Virtual Imaging ◽

Regulatory Evaluation

AbstractImaging clinical trials can be burdensome and often delay patient access to novel, high-quality medical devices. Tools for in silico imaging trials have significantly improved in sophistication and availability. Here, I describe some of the principal advantages of in silico imaging trials and enumerate five lessons learned during the design and execution of the first all-in silico virtual imaging clinical trial for regulatory evaluation (the VICTRE study).

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Targeting multiple conformations of SARS-CoV2 Papain-Like Protease for drug repositioning: An in-silico study

Computers in Biology and Medicine ◽

10.1016/j.compbiomed.2021.104295 ◽

2021 ◽

Vol 131 ◽

pp. 104295

Author(s):

Muhammad I. Ismail ◽

Hanan M. Ragab ◽

Adnan A. Bekhit ◽

Tamer M. Ibrahim

Keyword(s):

In Silico ◽

Drug Repositioning ◽

In Silico Study ◽

Multiple Conformations

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The Potency of Seaweed Sulfated Polysaccharides for the Correction of Hemostasis Disorders in COVID-19

Molecules ◽

10.3390/molecules26092618 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2618

Author(s):

Tatyana A. Kuznetsova ◽

Boris G. Andryukov ◽

Ilona D. Makarenkova ◽

Tatyana S. Zaporozhets ◽

Natalya N. Besednova ◽

...

Keyword(s):

Clinical Trials ◽

Therapeutic Potential ◽

Low Cost ◽

Clinical Manifestations ◽

Optimal Dose ◽

Monosaccharide Composition ◽

Structural Features ◽

Sulfated Polysaccharides ◽

Clinical Use ◽

Hemostasis System

Hemostasis disorders play an important role in the pathogenesis, clinical manifestations, and outcome of COVID-19. First of all, the hemostasis system suffers due to a complicated and severe course of COVID-19. A significant number of COVID-19 patients develop signs of hypercoagulability, thrombocytopenia, and hyperfibrinolysis. Patients with severe COVID-19 have a tendency toward thrombotic complications in the venous and arterial systems, which is the leading cause of death in this disease. Despite the success achieved in the treatment of SARS-CoV-2, the search for new effective anticoagulants, thrombolytics, and fibrinolytics, as well as their optimal dose strategies, continues to be relevant. The wide therapeutic potential of seaweed sulfated polysaccharides (PSs), including anticoagulant, thrombolytic, and fibrinolytic activities, opens up new possibilities for their study in experimental and clinical trials. These natural compounds can be important complementary drugs for the recovery from hemostasis disorders due to their natural origin, safety, and low cost compared to synthetic drugs. In this review, the authors analyze possible pathophysiological mechanisms involved in the hemostasis disorders observed in the pathological progression of COVID-19, and also focus the attention of researchers on seaweed PSs as potential drugs aimed to correction these disorders in COVID-19 patients. Modern literature data on the anticoagulant, antithrombotic, and fibrinolytic activities of seaweed PSs are presented, depending on their structural features (content and position of sulfate groups on the main chain of PSs, molecular weight, monosaccharide composition and type of glycosidic bonds, the degree of PS chain branching, etc.). The mechanisms of PS action on the hemostasis system and the issues of oral bioavailability of PSs, important for their clinical use as oral anticoagulant and antithrombotic agents, are considered. The combination of the anticoagulant, thrombolytic, and fibrinolytic properties, along with low toxicity and relative cheapness of production, open up prospects for the clinical use of PSs as alternative sources of new anticoagulant and antithrombotic compounds. However, further investigation and clinical trials are needed to confirm their efficacy.

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In silico environments augment clinical trials

IEEE Engineering in Medicine and Biology Magazine ◽

10.1109/51.486719 ◽

1996 ◽

Vol 15 (2) ◽

pp. 47-59 ◽

Cited By ~ 2

Author(s):

H.B. Sieburg

Keyword(s):

Clinical Trials ◽

In Silico

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Development of Chemical Compound Libraries for In Silico Drug Screening

Current Computer - Aided Drug Design ◽

10.2174/157340910791202450 ◽

2010 ◽

Vol 6 (2) ◽

pp. 90-102 ◽

Cited By ~ 2

Author(s):

Yoshifumi Fukunishi ◽

Masami Lintuluoto

Keyword(s):

Drug Screening ◽

In Silico ◽

Chemical Compound ◽

Compound Libraries

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In-silico drug screening method based on the protein–compound affinity matrix using the factor selection technique

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2006.12.028 ◽

2007 ◽

Vol 42 (7) ◽

pp. 966-976

Author(s):

Sukumaran Murali ◽

Shinichi Hojo ◽

Hideki Tsujishita ◽

Haruki Nakamura ◽

Yoshifumi Fukunishi

Keyword(s):

Drug Screening ◽

In Silico ◽

Screening Method ◽

Affinity Matrix ◽

Selection Technique

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Contemporary Clinical Use of Aspirin: Mechanisms of Action, Current Concepts, Unresolved Questions, and Future Perspectives

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-0041-1726096 ◽

2021 ◽

Author(s):

Mikael Christiansen ◽

Erik Lerkevang Grove ◽

Anne-Mette Hvas

Keyword(s):

Cardiovascular Disease ◽

Clinical Trials ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Bleeding Risk ◽

Clinical Use ◽

Action Current ◽

Potential Clinical Benefit ◽

Treatment Indications ◽

Prevention Of Cardiovascular Disease

AbstractThe ability of aspirin to inhibit platelet aggregation has positioned this agent within the most frequently used drugs worldwide. The aim of this article is to review the contemporary clinical use of aspirin and also to discuss unresolved issues not yet translated into clinical practice. Results from several clinical trials have led to strong guideline recommendations for aspirin use in the acute management and secondary prevention of cardiovascular disease. On the contrary, guidelines regarding aspirin use as primary prevention of cardiovascular disease are almost conservative, supported by recent trials reporting that the bleeding risk outweighs the potential benefits in most patients. In pregnancy, aspirin has proved efficient in preventing preeclampsia and small-for-gestational-age births in women at high risk, and is hence widely recommended in clinical guidelines. Despite the vast amount of clinical data on aspirin, several unresolved questions remain. Randomized trials have reported that aspirin reduces the risk of recurrent venous thromboembolism, but the clinical relevance remains limited, because direct oral anticoagulants are more effective. Laboratory studies suggest that a twice-daily dosing regimen or evening intake may lead to more efficient platelet inhibition, and the potential clinical benefit of such strategies is currently being explored in ongoing clinical trials. Enteric-coated formulations of aspirin are frequently used, but it remains unclear if they are safer and as efficient as plain aspirin. In the future, aspirin use after percutaneous coronary interventions might not be mandatory in patients who also need anticoagulant therapy, as several trials support shorter aspirin duration strategies. On the other hand, new treatment indications for aspirin will likely arise, as there is growing evidence that aspirin may reduce the risk of colorectal cancer and other types of cancer.

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