scholarly journals Multitarget Virtual Screening for Drug Repurposing in COVID19

2020 ◽  
Author(s):  
carlos oscar Sorzano ◽  
Enrique Crisman ◽  
Jose Maria Carazo ◽  
rafael leon
Keyword(s):  
Clinical Trials ◽  
Virtual Screening ◽  
Drug Screening ◽  
Binding Sites ◽  
Drug Repurposing ◽  
Viral Proteins ◽  
Binding Affinities ◽  
Compound Library ◽  
Screening Analysis ◽  
Virtual Drug Screening

Therapeutic or preventive research for coronavirus SARS-CoV2 is an extremely active topic of research since its outbreak in January 2020. In this paper we report the results from a virtual drug screening analysis that, to the best of our knowledge, is the widest work in terms of target proteins and compound library. Our study was focused on the repurposing of currently commercialized drugs, and especially those that can interact with multiple viral proteins and several binding sites within each protein. Additionally, we performed a second virtual screening analysis in which we compared our results to the predicted binding affinities for the drugs currently in clinical trials. We show that the best molecules in our screening compares favorably to those in clinical trials, suggesting their suitability for therapeutic or preventive applications.

scholarly journals Multitarget Virtual Screening for Drug Repurposing in COVID19

2020 ◽  
Author(s):  
carlos oscar Sorzano ◽  
Enrique Crisman ◽  
Jose Maria Carazo ◽  
rafael leon
Keyword(s):  
Clinical Trials ◽  
Virtual Screening ◽  
Drug Screening ◽  
Binding Sites ◽  
Drug Repurposing ◽  
Viral Proteins ◽  
Binding Affinities ◽  
Compound Library ◽  
Screening Analysis ◽  
Virtual Drug Screening

Therapeutic or preventive research for coronavirus SARS-CoV2 is an extremely active topic of research since its outbreak in January 2020. In this paper we report the results from a virtual drug screening analysis that, to the best of our knowledge, is the widest work in terms of target proteins and compound library. Our study was focused on the repurposing of currently commercialized drugs, and especially those that can interact with multiple viral proteins and several binding sites within each protein. Additionally, we performed a second virtual screening analysis in which we compared our results to the predicted binding affinities for the drugs currently in clinical trials. We show that the best molecules in our screening compares favorably to those in clinical trials, suggesting their suitability for therapeutic or preventive applications.

scholarly journals Multitarget Virtual Screening for Drug Repurposing in COVID19

2020 ◽  
Author(s):  
carlos oscar Sorzano ◽  
Enrique Crisman ◽  
Jose Maria Carazo ◽  
rafael leon
Keyword(s):  
Clinical Trials ◽  
Virtual Screening ◽  
Drug Screening ◽  
Binding Sites ◽  
Drug Repurposing ◽  
Viral Proteins ◽  
Binding Affinities ◽  
Compound Library ◽  
Screening Analysis ◽  
Virtual Drug Screening

Therapeutic or preventive research for coronavirus SARS-CoV2 is an extremely active topic of research since its outbreak in January 2020. In this paper we report the results from a virtual drug screening analysis that, to the best of our knowledge, is the widest work in terms of target proteins and compound library. Our study was focused on the repurposing of currently commercialized drugs, and especially those that can interact with multiple viral proteins and several binding sites within each protein. Additionally, we performed a second virtual screening analysis in which we compared our results to the predicted binding affinities for the drugs currently in clinical trials. We show that the best molecules in our screening compares favorably to those in clinical trials, suggesting their suitability for therapeutic or preventive applications.

scholarly journals Docking study of Selected Vinis vitifera seeds constituents on Dengue viral proteins – An In Silico approach

2018 ◽  
Vol 6 (04) ◽  
pp. 25-31
Author(s):  
M. Bhavya ◽  
M. Ramya ◽  
N. Nagarjun ◽  
Nagarathna Amresh ◽  
Balasubramanian Sathyamurthy
Keyword(s):  
Virtual Screening ◽  
Dengue Virus ◽  
In Silico ◽  
Viral Proteins ◽  
Docking Study ◽  
Virus Protein ◽  
Binding Affinities ◽  
Amino Acid Residues ◽  
Protein Targets ◽  
Docking Approach

Dengue is a mosquito-borne systemic viral infection caused by any of the four antigenically related dengue viruses (DENV).The dengue virus belongs to the Flaviviridae family of viruses that cause diseases in humans.A virtual screening analysis of phytochemical structures with dengue virus protein targets has been carried out using a molecular docking approach with vins vinifera seeds. Grapes (Vinis vitifera) are believed to have health benefits due to their antioxidant activity and polyphenols. In this study we examined the binding affinities of 14 ligands with seven non structural Dengu viral proteins through In Silico methods like virtual screening and docking process which showed that compound F and compound N had high binding efficiencies with these proteins along with the type of hydrogen bonds and their respective amino acid residues at their docked sites.

scholarly journals A Machine Learning-Enabled Pipeline for Large-Scale Virtual Drug Screening

2021 ◽  
Author(s):  
Aayush Gupta ◽  
Huan-Xiang Zhou
Keyword(s):  
Breast Cancer ◽  
Neural Network ◽  
Machine Learning ◽  
Drug Discovery ◽  
Virtual Screening ◽  
Drug Screening ◽  
Drug Target ◽  
Large Scale ◽  
False Positives ◽  
Virtual Drug Screening

Virtual screening is receiving renewed attention in drug discovery, but progress is hampered by challenges on two fronts: handling the ever increasing sizes of libraries of drug-like compounds, and separating true positives from false positives. Here we developed a machine learning-enabled pipeline for large-scale virtual screening that promises breakthroughs on both fronts. By clustering compounds according to molecular properties and limited docking against a drug target, the full library was trimmed by 10-fold; the remaining compounds were then screened individually by docking; and finally a dense neural network was trained to classify the hits into true and false positives. As illustration, we screened for inhibitors against RPN11, the deubiquitinase subunit of the proteasome and a drug target for breast cancer.

scholarly journals In silico discovery and biological validation of ligands of FAD synthase, a promising new antimicrobial target

2020 ◽  
Author(s):  
Isaias Lans ◽  
Ernesto Anoz-Carbonell ◽  
Karen Palacio-Rodríguez ◽  
José Antonio Aínsa ◽  
Milagros Medina ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Drug Screening ◽  
In Silico ◽  
Flavin Adenine Dinucleotide ◽  
Bacterial Species ◽  
Therapeutic Targets ◽  
Cost Effective ◽  
Md Simulations ◽  
Compound Library ◽  
Corynebacterium Ammoniagenes

AbstractNew treatments for diseases caused by antimicrobial-resistant microorganisms can be developed by identifying unexplored therapeutic targets and by designing efficient drug screening protocols. In this study, we have screened a library of compounds to find ligands for the flavin-adenine dinucleotide synthase (FADS) -a potential target for drug design against tuberculosis and pneumonia- by implementing a new and efficient virtual screening protocol. The protocol has been developed for the in silico search of ligands of unexplored therapeutic targets, for which limited information about ligands or ligand-receptor structures is available. It implements an integrative funnel-like strategy with filtering layers that increase in computational accuracy. The protocol starts with a pharmacophore-based virtual screening strategy that uses ligand-free receptor conformations from molecular dynamics (MD) simulations. Then, it performs a molecular docking stage using several docking programs and an exponential consensus ranking strategy. The last filter, samples the conformations of compounds bound to the target using MD simulations. The MD conformations are scored using several traditional scoring functions in combination with a newly-proposed score that takes into account the fluctuations of the molecule with a Morse-based potential. The protocol was optimized and validated using a compound library with known ligands of the Corynebacterium ammoniagenes FADS. Then, it was used to find new FADS ligands from a compound library of 14,000 molecules. A small set of 17 in silico filtered molecules were tested experimentally. We identified five inhibitors of the activity of the flavin adenylyl transferase mononucleotide of the FADS, and some of them were able to inhibit growth of three bacterial species: Corynebacterium ammoniagenes, Mycobacterium tuberculosis, and Streptococcus pneumoniae, where the former two are human pathogens. Overall, the results show that the integrative VS protocol is a cost-effective solution for the discovery of ligands of unexplored therapeutic targets.Author summaryDeveloping cures for antimicrobial-resistant microorganisms is a pressing necessity. Addressing this problem requires the discovery of novel therapeutic targets -for example, bacterial proteins with no human homologues- and the development of cost-effective drug screening protocols. In this work, we tackled the problem on both sides. We developed an efficient and successful integrative computational protocol for screening inhibitory-molecules for unexplored targets. We used it to discover five novel inhibitors of flavin-adenine dinucleotide synthase (FADS), a promising protein target of pathogens causing tuberculosis and pneumonia.

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.

scholarly journals Therapeutic clinical trials to combat COVID-19 pandemic in India: analysis from trial registry

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Angelika Batta ◽  
Raj Khirasaria ◽  
Vinod Kapoor ◽  
Deepansh Varshney
Keyword(s):  
Clinical Trials ◽  
De Novo ◽  
Treatment Options ◽  
Drug Repurposing ◽  
Trial Registry ◽  
Therapeutic Treatment ◽  
Clinical Trial Registry ◽  
Clear Cut ◽  
Therapeutic Trials ◽  
Microsoft Office

AbstractObjectivesWith the emergence of Novel corona virus, hunt for finding a preventive and therapeutic treatment options has already begun at a rapid pace with faster clinical development programs. The present study was carried out to give an insight of therapeutic interventional trials registered under clinical trial registry of India (CTRI) for COVID-19 pandemic.MethodsAll trials registered under CTRI were evaluated using keyword “COVID” from its inception till 9th June 2020. Out of which, therapeutic interventional studies were chosen for further analysis. Following information was collected for each trial: type of therapeutic intervention (preventive/therapeutic), treatment given, no. of centers (single center/multicentric), type of institution (government/private), study design (randomized/single-blinded/double-blinded) and sponsors (Government/private). Microsoft Office Excel 2007 was used for tabulation and analysis.ResultsThe search yielded total of 205 trials, out of which, 127 (62%) trials were interventional trials. Out of these, 71 (56%) were AYUSH interventions, 36 (28.3%) tested drugs, 9 (7%) tested a nondrug intervention, rest were nutraceuticals and vaccines. About 66 (56%) were therapeutic trials. Majority were single-centered trials, i.e. 87 (73.7%). Trials were government funded in 57 (48.3%) studies. Majority were randomized controlled trials, i.e. 67 (56.8%). AYUSH preparations included AYUSH-64, Arsenic Album, SamshamaniVati etc.ConclusionsThe number of therapeutic interventional clinical trials was fair in India. A clear-cut need exists for an increase in both quantity and quality of clinical trials for COVID-19. Drug repurposing approach in all systems of medicine can facilitate prompt clinical decisions at lower costs than de novo drug development.

scholarly journals Drug Repurposing Opportunities in Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 14 (3) ◽  
pp. 280
Author(s):  
Rita Rebelo ◽  
Bárbara Polónia ◽  
Lúcio Lara Santos ◽  
M. Helena Vasconcelos ◽  
Cristina P. R. Xavier
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Pancreatic Ductal Adenocarcinoma ◽  
De Novo ◽  
Drug Repurposing ◽  
Metastatic Tumor ◽  
Therapeutic Options ◽  
Ductal Adenocarcinoma ◽  
Clinical Indication ◽  
Novel Treatments

Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest tumors worldwide. The diagnosis is often possible only in the latter stages of the disease, with patients already presenting an advanced or metastatic tumor. It is also one of the cancers with poorest prognosis, presenting a five-year survival rate of around 5%. Treatment of PDAC is still a major challenge, with cytotoxic chemotherapy remaining the basis of systemic therapy. However, no major advances have been made recently, and therapeutic options are limited and highly toxic. Thus, novel therapeutic options are urgently needed. Drug repurposing is a strategy for the development of novel treatments using approved or investigational drugs outside the scope of the original clinical indication. Since repurposed drugs have already completed several stages of the drug development process, a broad range of data is already available. Thus, when compared with de novo drug development, drug repurposing is time-efficient, inexpensive and has less risk of failure in future clinical trials. Several repurposing candidates have been investigated in the past years for the treatment of PDAC, as single agents or in combination with conventional chemotherapy. This review gives an overview of the main drugs that have been investigated as repurposing candidates, for the potential treatment of PDAC, in preclinical studies and clinical trials.

scholarly journals Discovery of a Bradykinin B2 Partial Agonist Profile of Raloxifene in a Drug Repurposing Campaign

2020 ◽  
Vol 22 (1) ◽  
pp. 257
Author(s):  
Patricia Gomez-Gutierrez ◽  
Juan J. Perez
Keyword(s):  
Virtual Screening ◽  
Molecular Mechanisms ◽  
Partial Agonist ◽  
Drug Repurposing ◽  
Cytokine Storm ◽  
Bradykinin Receptors ◽  
Screening Process ◽  
Bradykinin Antagonists ◽  
Illness Progression

Covid-19 urges a deeper understanding of the underlying molecular mechanisms involved in illness progression to provide a prompt therapeutical response with an adequate use of available drugs, including drug repurposing. Recently, it was suggested that a dysregulated bradykinin signaling can trigger the cytokine storm observed in patients with severe Covid-19. In the scope of a drug repurposing campaign undertaken to identify bradykinin antagonists, raloxifene was identified as prospective compound in a virtual screening process. The pharmacodynamics profile of raloxifene towards bradykinin receptors is reported in the present work, showing a weak selective partial agonist profile at the B2 receptor. In view of this new profile, its possible use as a therapeutical agent for the treatment of severe Covid-19 is discussed.

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