scholarly journals Virus-CKB: an integrated bioinformatics platform and analysis resource for COVID-19 research

2020 ◽  
Author(s):  
Zhiwei Feng ◽  
Maozi Chen ◽  
Tianjian Liang ◽  
Mingzhe Shen ◽  
Hui Chen ◽  
...  
Keyword(s):  
Web Applications ◽  
Protein Targets ◽  
Computing Platform ◽  
Chemical Agents ◽  
Rapid Spread ◽  
One Stop ◽  
Approved Drugs ◽  
Computational Systems ◽  
Symbol Display ◽  
Fda Approved Drugs

Abstract Given the scale and rapid spread of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is an urgent need for medicines that can help before vaccines are available. In this study, we present a viral-associated disease-specific chemogenomics knowledgebase (Virus-CKB) and apply our computational systems pharmacology-target mapping to rapidly predict the FDA-approved drugs which can quickly progress into clinical trials to meet the urgent demand of the COVID-19 outbreak. Virus-CKB reuses the underlying platform of our DAKB-GPCRs but adds new features like multiple-compound support, multi-cavity protein support and customizable symbol display. Our one-stop computing platform describes the chemical molecules, genes and proteins involved in viral-associated diseases regulation. To date, Virus-CKB archived 65 antiviral drugs in the market, 107 viral-related targets with 189 available 3D crystal or cryo-EM structures and 2698 chemical agents reported for these target proteins. Moreover, Virus-CKB is implemented with web applications for the prediction of the relevant protein targets and analysis and visualization of the outputs, including HTDocking, TargetHunter, BBB predictor, NGL Viewer, Spider Plot, etc. The Virus-CKB server is accessible at https://www.cbligand.org/g/virus-ckb.

Selection of Active Antiviral Compounds Against Covid-19 Disease Targeting Coronavirus Endoribonuclease Nendou/NSP15 Via Ligand- Based Virtual Screening and Molecular Docking

2020 ◽  
Vol 17 ◽  
Author(s):  
Gaurav Joshi ◽  
Ramarao Poduri
Keyword(s):  
Virtual Screening ◽  
Drug Repurposing ◽  
Antiviral Compounds ◽  
Clinical Level ◽  
Rapid Spread ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Selection Of

Background: The rapid spread of SARS-CoV-2 has caused havoc and panic among individuals, which has further worsened due to the unavailability of a proven drug(s) regime. Objective: The current work involves drug repurposing from the pool of USFDA approved drugs involving in silico virtual screening technique against Covid-19. Methods: Methodology involves virtual screening of 8548 FDA approved drugs against target protein endoribonuclease NendoU (Nsp15) (PDB ID: 6VWW). Results: Virtual screening-based analysis enabled us to identify four drugs, Eprosartan, Inarigivir soproxil, Foretinib, and DB01813 that could plausibly target Nsp15 against Covid-19 disease. Conclusion: The work offers the scope to corroborate the findings via in vitro and in vivo techniques to identify the potential of selected leads against Covid-19. The outcome may also help in tracing their molecular mechanism(s) in addition to their development at the clinical level in the future.

scholarly journals Crystal-Structures-Guided Design of Fragment-Based Drugs for Inhibiting the Main Protease of SARS-CoV-2

2020 ◽  
Author(s):  
Binquan Luan ◽  
Tien Huynh
Keyword(s):  
Binding Free Energy ◽  
Dynamics Simulation ◽  
Drug Molecule ◽  
Protein Targets ◽  
Main Protease ◽  
Potent Drug ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Efficacious Drug ◽  
Better Than

Abstract Since the beginning of the COVID-19 pandemic, researchers and scientists across the globe are racing to find a cure for the highly contagious infectious disease caused by the SARS-CoV-2 virus. Despite many promising ongoing progress, there are currently no FDA approved drugs to treat infected patients. Among the various protein targets of SARS-CoV-2 virus, the main protease (Mpro) has attracted most interests. Recently, the crowdsourcing of drug discovery for inhibiting Mpro have yielded a plenty of drug fragments resolved inside the active site of Mpro via the crystallography method. Following the principle of fragment-based drug design (FBDD), we are motivated to design a potent drug molecule through merging several of these newly discovered drug fragments. Among various designed ligands, we found that B19 by merging three fragments JFM, U0P and HWH is the most stable one, evidenced through extensive (~10 μs totally) all-atom molecular dynamics simulation. We further estimated that the binding free energy of B19 is comparable or even a little better than that of a native protein ligand processed by Mpro. Our promising results suggest that B19 can potentially be an efficacious drug molecule for inhibiting Mpro of SARS-CoV-2.

scholarly journals Computational Drug Repurposing Studies on SARS-CoV-2 Protein Targets

2020 ◽  
Author(s):  
Guangfeng Zhou ◽  
Lance Stewart ◽  
Gabriella Reggiano ◽  
Frank DiMaio
Keyword(s):  
Experimental Validation ◽  
Rna Binding ◽  
Drug Repurposing ◽  
Protein Targets ◽  
Priority List ◽  
Computational Docking ◽  
Docking Protocol ◽  
Approved Drugs ◽  
Aids Drugs ◽  
Fda Approved Drugs

To contribute to the combat of COVID-2019, we applied structure-based computational docking screens using flexible docking protocol of Rosetta GALigandDock against multiple potential SARS-CoV-2 protein targets, including the Nsp5 3-chymotrypsin-like protease (3CLpro), the Nsp3 ADP ribose phosphatase, the Nsp15 Endoribonuclease, the RNA binding domain of nucleocapsid phosphoprotein, the Nsp16 2'-O-MTase, Nsp14, and Nsp12 RNA-dependent RNA polymerase. Screening against a re-purposing library of 8,395 FDA approved drugs at various stages of drug development and various natural products from DrugBank, we found a total of 124 putative inhibitors with predicted binding ∆G less than -8.9 kcal/mol, including HIV-AIDS drugs Nelfinavir and Tipranavir, targeting 3Clpro with ∆G=-18.8 kcal/mol and ∆G=-16.6 kcal/mol respectively. These primarily involve binders to the Nsp5 3CLpro (37 hits) and the Nsp3 ADP ribose phosphatase (36 hits), with smaller numbers of hits to other targets. These small molecule putative inhibitors suggest a possible avenue for drug repurposing, and the identified compounds should serve as a high-priority list for experimental validation via co-crystallization, enzymatic and cell based assays.

scholarly journals MCCS: a novel recognition pattern-based method for fast track discovery of anti-SARS-CoV-2 drugs

2020 ◽  
Author(s):  
Zhiwei Feng ◽  
Maozi Chen ◽  
Ying Xue ◽  
Tianjian Liang ◽  
Hui Chen ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Potential Treatment ◽  
Traditional Research ◽  
Rapid Spread ◽  
Novel Strategy ◽  
Approved Drugs ◽  
Key Residues ◽  
Fda Approved Drugs ◽  
Anti Hiv ◽  
Positive Results

Abstract Given the scale and rapid spread of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, or 2019-nCoV), there is an urgent need to identify therapeutics that are effective against COVID-19 before vaccines are available. Since the current rate of SARS-CoV-2 knowledge acquisition via traditional research methods is not sufficient to match the rapid spread of the virus, novel strategies of drug discovery for SARS-CoV-2 infection are required. Structure-based virtual screening for example relies primarily on docking scores and does not take the importance of key residues into consideration, which may lead to a significantly higher incidence rate of false-positive results. Our novel in silico approach, which overcomes these limitations, can be utilized to quickly evaluate FDA-approved drugs for repurposing and combination, as well as designing new chemical agents with therapeutic potential for COVID-19. As a result, anti-HIV or antiviral drugs (lopinavir, tenofovir disoproxil, fosamprenavir and ganciclovir), antiflu drugs (peramivir and zanamivir) and an anti-HCV drug (sofosbuvir) are predicted to bind to 3CLPro in SARS-CoV-2 with therapeutic potential for COVID-19 infection by our new protocol. In addition, we also propose three antidiabetic drugs (acarbose, glyburide and tolazamide) for the potential treatment of COVID-19. Finally, we apply our new virus chemogenomics knowledgebase platform with the integrated machine-learning computing algorithms to identify the potential drug combinations (e.g. remdesivir+chloroquine), which are congruent with ongoing clinical trials. In addition, another 10 compounds from CAS COVID-19 antiviral candidate compounds dataset are also suggested by Molecular Complex Characterizing System with potential treatment for COVID-19. Our work provides a novel strategy for the repurposing and combinations of drugs in the market and for prediction of chemical candidates with anti-COVID-19 potential.

scholarly journals Computational Drug Repurposing Studies on SARS-CoV-2 Protein Targets

2020 ◽  
Author(s):  
Guangfeng Zhou ◽  
Lance Stewart ◽  
Gabriella Reggiano ◽  
Frank DiMaio
Keyword(s):  
Experimental Validation ◽  
Rna Binding ◽  
Drug Repurposing ◽  
Protein Targets ◽  
Priority List ◽  
Computational Docking ◽  
Docking Protocol ◽  
Approved Drugs ◽  
Aids Drugs ◽  
Fda Approved Drugs

To contribute to the combat of COVID-2019, we applied structure-based computational docking screens using flexible docking protocol of Rosetta GALigandDock against multiple potential SARS-CoV-2 protein targets, including the Nsp5 3-chymotrypsin-like protease (3CLpro), the Nsp3 ADP ribose phosphatase, the Nsp15 Endoribonuclease, the RNA binding domain of nucleocapsid phosphoprotein, the Nsp16 2'-O-MTase, Nsp14, and Nsp12 RNA-dependent RNA polymerase. Screening against a re-purposing library of 8,395 FDA approved drugs at various stages of drug development and various natural products from DrugBank, we found a total of 124 putative inhibitors with predicted binding ∆G less than -8.9 kcal/mol, including HIV-AIDS drugs Nelfinavir and Tipranavir, targeting 3Clpro with ∆G=-18.8 kcal/mol and ∆G=-16.6 kcal/mol respectively. These primarily involve binders to the Nsp5 3CLpro (37 hits) and the Nsp3 ADP ribose phosphatase (36 hits), with smaller numbers of hits to other targets. These small molecule putative inhibitors suggest a possible avenue for drug repurposing, and the identified compounds should serve as a high-priority list for experimental validation via co-crystallization, enzymatic and cell based assays.

Comparing the Metabolome of a Caribbean Sponge to 420 FDA Approved Drugs, a Molecular Networking Approach

Planta Medica ◽  
2013 ◽  
Vol 79 (10) ◽  
Author(s):  
H Houson ◽  
J Schlesser ◽  
J Beverage ◽  
V Macherla ◽  
E Esquenazi
Keyword(s):  
Molecular Networking ◽  
Approved Drugs ◽  
Fda Approved Drugs

Targeting COVID-19 in Parkinson’s patients: Drugs repurposed.

2020 ◽  
Vol 27 ◽  
Author(s):  
Firoz Anwar ◽  
Salma Naqvi ◽  
Fahad A. Al-Abbasi ◽  
Nauroz Neelofar ◽  
Vikas Kumar ◽  
...  
Keyword(s):  
Day Treatment ◽  
Treatment Options ◽  
Developed Countries ◽  
Methyl Transferase ◽  
Comt Inhibitors ◽  
Mao B ◽  
Pharmacokinetic Properties ◽  
Us Fda ◽  
Approved Drugs ◽  
Fda Approved Drugs

: The last couple of months have witnessed the world in a state of virtual standstill. The SARS-CoV-2 virus has overtaken globe to economic and social lockdown. Many patients with COVID-19 have compromised immunity, especially in an aged population suffering from Parkinson disease (PD). Alteration in dopaminergic neurons or deficiency of dopamine in PD patients is the most common symptoms affecting 1% population above the age of 60 years. The compromised immune system and inflammatory manifestation in PD patients make them an easy target. The most common under trial drugs for COVID-19 are Remdesivir, Favipiravir, Chloroquine and Hydroxychloroquine, Azithromycin along with adjunct drugs like Amantadine with some monoclonal antibodies. : Presently, clinically US FDA approved drugs in PD includes Levodopa, catechol-O-methyl transferase (COMT) inhibitors, (Entacapone and Tolcapone), Dopamine agonists (Bromocriptine, Ropinirole, Pramipexole, and Rotigotine), Monoamine oxidase B (MAO-B) inhibitors (Selegiline and Rasagiline), Amantadine and Antimuscarinic drugs. The drugs have established mechanism of action on PD patients with known pharmacodynamics and pharmacokinetic properties along with dose and adverse effects. : Conclusion and relevance of this review focus on the drugs that can be tried for the PD patients with SAR CoV-2 infection, in particular, Amantadine approved by all developed countries a common drug possessing both antiviral properties by downregulation of CTSL, lysosomal pathway disturbance and change in pH necessary to uncoat the viral proteins and antiParkinson properties. The significant prognostic adverse effect of SARS-CoV-2 on PD and the present-day treatment options, clinical presentation and various mechanism is warrant need of the hour.

Pd Catalyzed N1/N4 Arylation of Piperazine for Synthesis of Drugs, Biological and Pharmaceutical Targets: An Overview of Buchwald Hartwig Amination Reaction of Piperazine in Drug Synthesis

2018 ◽  
Vol 15 (2) ◽  
pp. 208-220 ◽  
Author(s):  
Vaibhav Mishra ◽  
Tejpal Singh Chundawat
Keyword(s):  
Bond Formation ◽  
Catalyst Design ◽  
Biologically Active ◽  
Reaction Conditions ◽  
Biological Targets ◽  
Amination Reaction ◽  
Drug Synthesis ◽  
Substituted Piperazine ◽  
Approved Drugs ◽  
Fda Approved Drugs

Background: Substituted piperazine heterocycles are among the most significant structural components of pharmaceuticals. N1/N4 substituted piperazine containing drugs and biological targets are ranked 3rd in the top most frequent nitrogen heterocycles in U.S. FDA approved drugs. The high demand of N1/N4 substituted piperazine containing biologically active compounds and U.S. FDA approved drugs, has prompted the development of Pd catalyzed C-N bond formation reactions for their synthesis. Buchwald-Hartwig reaction is the key tool for the synthesis of these compounds. Objective: This review provides strategies for Pd catalyzed C-N bond formation at N1/N4 of piperazine in the synthesis of drugs and biological targets with diverse use of catalyst-ligand system and reaction parameters. Conclusion: It is clear from the review that a vast amount of work has been done in the synthesis of N1/N4 substituted piperazine containing targets under the Pd catalyzed Buchwald-Hartwig amination of aryl halides by using different catalyst-ligand systems. These methods have become increasingly versatile as a result of innovation in catalyst design and improvements in reaction conditions. This review gives an overview of recent utilization of Buchwald-Hartwig amination reaction in drug/target synthesis.

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