scholarly journals In silico and in vitro screening of FDA-approved drugs for potential repurposing against tuberculosis

2017 ◽  
Author(s):  
Sridharan Brindha ◽  
Jagadish Chandrabose Sundaramurthi ◽  
Savariar Vincent ◽  
Devadasan Velmurugan ◽  
John Joel Gnanadoss
Keyword(s):  
In Silico ◽  
Drug Targets ◽  
Luciferase Reporter ◽  
Synergistic Activity ◽  
Resistant Strains ◽  
Approved Drugs ◽  
Clinical Conditions ◽  
Drug Resistant Strains ◽  
Fda Approved Drugs

AbstractMotivationRepurposing of known drugs to newer clinical conditions is a promising avenue for finding novel therapeutic applications for tuberculosis.MethodsWe performed docking-based virtual screening for 1554 known drugs against two of the potential drug targets, namely trpD and coaA of M. tuberculosis. In the first round of in silico screening we used rigid docking using Glide and AutoDock Vina. We subjected the consistently ranked drugs for induced-fit docking by these tools against the same target proteins. We performed luciferase reporter phage (LRP) assay to determine the biological activity of five selected drugs against M. tuberculosis.ResultsWe observed lymecycline and cefpodoxime to be active against drug susceptible and drug resistant strains of M. tuberculosis. In addition, lymecycline and cefpodoxime showed synergistic activity with rifampin and isoniazid against M. tuberculosis.ConclusionOur results suggest that lymecycline and cefpodoxime have potential to be repurposed for the treatment of tuberculosis.

Potential Papain-like Protease Inhibitors against COVID-19: A Comprehensive In Silico Based Review

2021 ◽  
Vol 25 ◽  
Author(s):  
Neetu Agrawal ◽  
Shilpi Pathak ◽  
Ahsas Goyal
Keyword(s):  
In Silico ◽  
Chemical Compounds ◽  
Potential Candidate ◽  
In Vivo Experiments ◽  
Drug Databases ◽  
In Silico Studies ◽  
Approved Drugs ◽  
Fda Approved Drugs

: The entire world has been in a battle against the COVID-19 pandemic since its first appearance in December 2019. Thus researchers are desperately working to find an effective and safe therapeutic agent for its treatment. The multifunctional coronavirus enzyme papain-like protease (PLpro) is a potential target for drug discovery to combat the ongoing pandemic responsible for cleavage of the polypeptide, deISGylation, and suppression of host immune response. The present review collates the in silico studies performed on various FDA-approved drugs, chemical compounds, and phytochemicals from various drug databases and represents the compounds possessing the potential to inhibit PLpro. Thus this review can provide quick access to a potential candidate to medicinal chemists to perform in vitro and in vivo experiments who are thriving to find the effective agents for the treatment of COVID-19.

scholarly journals Host-Directed FDA-Approved Drugs with Antiviral Activity against SARS-CoV-2 Identified by Hierarchical In Silico/In Vitro Screening Methods

2021 ◽  
Vol 14 (4) ◽  
pp. 332
Author(s):  
Tiziana Ginex ◽  
Urtzi Garaigorta ◽  
David Ramírez ◽  
Victoria Castro ◽  
Vanesa Nozal ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Viral Entry ◽  
In Silico ◽  
Screening Methods ◽  
Speed Up ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Shed Light ◽  
Virtual Screening Approach

The unprecedent situation generated by the COVID-19 global emergency has prompted us to actively work to fight against this pandemic by searching for repurposable agents among FDA approved drugs to shed light into immediate opportunities for the treatment of COVID-19 patients. In the attempt to proceed toward a proper rationalization of the search for new antivirals among approved drugs, we carried out a hierarchical in silico/in vitro protocol which successfully combines virtual and biological screening to speed up the identification of host-directed therapies against COVID-19 in an effective way. To this end a multi-target virtual screening approach focused on host-based targets related to viral entry, followed by the experimental evaluation of the antiviral activity of selected compounds, has been carried out. As a result, five different potentially repurposable drugs interfering with viral entry—cepharantine, clofazimine, metergoline, imatinib and efloxate—have been identified.

Repurposing FDA-approved Drugs Targeting SARS-CoV2 3CLpro: a study by applying Virtual Screening, Molecular Dynamics, MM-PBSA Calculations and Covalent Docking

2022 ◽  
Vol 19 ◽  
Author(s):  
Igor José dos Santos Nascimento ◽  
Thiago Mendonça de Aquino ◽  
Edeildo Ferreira da Silva-Júnior
Keyword(s):  
Molecular Dynamics ◽  
Virtual Screening ◽  
In Silico ◽  
Structural Integrity ◽  
Inhibition Mechanism ◽  
Zinc Database ◽  
Covalent Docking ◽  
Approved Drugs ◽  
Fda Approved Drugs

Background: Since the end of 2019, the etiologic agent SAR-CoV-2 responsible for one of the most significant epidemics in history has caused severe global economic, social, and health damages. The drug repurposing approach and application of Structure-based Drug Discovery (SBDD) using in silico techniques are increasingly frequent, leading to the identification of several molecules that may represent promising potential. Method: In this context, here we use in silico methods of virtual screening (VS), pharmacophore modeling (PM), and fragment-based drug design (FBDD), in addition to molecular dynamics (MD), molecular mechanics/Poisson-Boltzmann surface area (MM -PBSA) calculations, and covalent docking (CD) for the identification of potential treatments against SARS-CoV-2. We initially validated the docking protocol followed by VS in 1,613 FDA-approved drugs obtained from the ZINC database. Thus, we identified 15 top hits, of which three of them were selected for further simulations. In parallel, for the compounds with a fit score value ≤ of 30, we performed the FBDD protocol, where we designed 12 compounds Result: By applying a PM protocol in the ZINC database, we identified three promising drug candidates. Then, the 9 top hits were evaluated in simulations of MD, MM-PBSA, and CD. Subsequently, MD showed that all identified hits showed stability at the active site without significant changes in the protein's structural integrity, as evidenced by the RMSD, RMSF, Rg, SASA graphics. They also showed interactions with the catalytic dyad (His41 and Cys145) and other essential residues for activity (Glu166 and Gln189) and high affinity for MM-PBSA, with possible covalent inhibition mechanism. Conclution: Finally, our protocol helped identify potential compounds wherein ZINC896717 (Zafirlukast), ZINC1546066 (Erlotinib), and ZINC1554274 (Rilpivirine) were more promising and could be explored in vitro, in vivo, and clinical trials to prove their potential as antiviral agents.

scholarly journals In-silico identification of natural antiviral drug against SARS-CoV-2 and comparison with potential FDA approved drug targets

2020 ◽  
Vol 3 (4) ◽  
pp. 1-11
Author(s):  
SARRA AKERMI ◽  
Neha Lohar ◽  
Subrata Sinha ◽  
Surabhi Johari ◽  
Sunil Jayant ◽  
...  
Keyword(s):  
Free Energy ◽  
In Silico ◽  
High Throughput Screening ◽  
Drug Targets ◽  
Antiviral Drug ◽  
Spike Protein ◽  
Plant Metabolites ◽  
Secondary Plant Metabolites ◽  
Approved Drugs ◽  
Fda Approved Drugs

Antimalarial drugs Chloroquine and Hydroxychloroquine have garnered most attention recently as a successful remedy for COVID19. However, the use of these drugs is still questionable due to its undetermined efficacy and side effects. The present study utilizes in-silico high throughput screening of FDA approved antiviral compounds and secondary plant metabolites against spike protein of novel coronavirus (SARS-CoV-2). This target was chosen because it is instrumental in entry of virus into human cells. It is observed that the plant compound Tocopheryl-curcumin has more affinity for spike protein of SARS-CoV-2 in comparison to the majority of FDA approved drugs. Tocopheryl-curcumin binds with the binding site of RBD domain of spike protein (6VSB, chain A) with free energy (∆G) of binding of -11.20 kcal/mol and makes strong hydrogen bonds with amino acid residues of S366, V367, L368, S373, and K529. Among the FDA approved drugs, Pibrentasvir obtains top rank with free energy (∆G) of binding of -9.69 kcal/mol. whereas; surprisingly Chloroquine (-6.87 kcal/mol) and Hydroxychloroquine (-7.24 kcal/mol) ranked lower in our docking study. The toxicity prediction by VEGA predicts that tocopheryl-curcumin shows no toxicity as compared to FDA approved drugs. Therefore, we infer that the plant-based tocopheryl-curcumin could be considered as potential and safer drug against COVID 19 disease as compared to chemical based drugs.

scholarly journals Host-directed FDA-approved drugs with antiviral activity against SARS-CoV-2 identified by hierarchical in silico/in vitro screening methods

2020 ◽  
Author(s):  
Tiziana Ginex ◽  
Urtzi Garaigorta ◽  
David Ramírez ◽  
Victoria Castro ◽  
Vanesa Nozal ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Viral Entry ◽  
In Silico ◽  
Drug Repurposing ◽  
Screening Methods ◽  
Speed Up ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Virtual Screening Approach

AbstractThe unprecedent situation generated by the COVID-19 global emergency has prompted scientists around the world to actively work to fight against this pandemic. In this sense, it is remarkable the number of drug repurposing efforts trying to shed light into the COVID-19 patients’ treatment.In the attempt to proceed toward a proper rationalization of the search for new antivirals among approved drugs, we carried out a hierarchical in silico/in vitro protocol which successfully combines virtual and biological screening to speed up the identification of host-directed therapies against COVID-19 in an effective way.A successful combination of a multi-target virtual screening approach focused on host-based targets related to viral entry and experimental evaluation of the antiviral activity of selected compounds has been carried out. As a result, three different potentially repurposable drugs interfering with viral entry, cepharantine, imatinib and efloxate, have been identified.

Repurposing of auranofin against bacterial infections: An In silico and In vitro study

2020 ◽  
Vol 16 ◽  
Author(s):  
Nidhi Sharma ◽  
Arti Singh ◽  
Ruchika Sharma ◽  
Anoop Kumar
Keyword(s):  
Broad Spectrum ◽  
In Silico ◽  
Antibacterial Agent ◽  
Bacterial Infections ◽  
In Vitro Assays ◽  
Infection Model ◽  
Synergistic Activity ◽  
Bacterial Strains ◽  
Molecular Docking Study

Aim: The aim of the study was to find out the role of auranofin as a promising broad spectrum antibacterial agent. Methods: In-vitro assays (Percentage growth retardation, Bacterial growth kinetics, Biofilm formation assay) and In-silico study (Molegro virtual docker (MVD) version 6.0 and Molecular operating environment (MOE) version 2008.10 software). Results: The in vitro assays have shown that auranofin has good antibacterial activity against Gram positive and Gram negative bacterial strains. Further, auranofin has shown synergistic activity in combination with ampicillin against S. aureus and B. subtilis whereas in combination with neomycin has just shown additive effect against E. coli, P. aeruginosa and B. pumilus. In vivo results have revealed that auranofin alone and in combination with standard drugs significantly decreased the bioburden in zebrafish infection model as compared to control. The molecular docking study have shown good interaction of auranofin with penicillin binding protein (2Y2M), topoisomerase (3TTZ), UDP-3-O-[3- hydroxymyristoyl] N-acetylglucosaminedeacetylase (3UHM), cell adhesion protein (4QRK), β-lactamase (5CTN) and arylsulphatase (1HDH) enzyme as that of reference ligand which indicate multimodal mechanism of action of auranofin. Finally, MTT assay has shown non-cytotoxic effect of auranofin. Conclusion: In conclusion, auranofin in combination with existing antibiotics could be developed as a broad spectrum antibacterial agent; however, further studies are required to confirm its safety and efficacy. This study provides possibility of use of auranofin apart from its established therapeutic indication in combination with existing antibiotics to tackle the problem of resistance.

scholarly journals Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Vicky Mody ◽  
Joanna Ho ◽  
Savannah Wills ◽  
Ahmed Mawri ◽  
Latasha Lawson ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Dynamics Simulation ◽  
Simulation Studies ◽  
Inhibitory Effects ◽  
Major Threat ◽  
Main Protease ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Computational Molecular Modeling

AbstractEmerging outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is a major threat to public health. The morbidity is increasing due to lack of SARS-CoV-2 specific drugs. Herein, we have identified potential drugs that target the 3-chymotrypsin like protease (3CLpro), the main protease that is pivotal for the replication of SARS-CoV-2. Computational molecular modeling was used to screen 3987 FDA approved drugs, and 47 drugs were selected to study their inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme in vitro. Our results indicate that boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin exhibited inhibitory effect towards 3CLpro enzymatic activity. The 100 ns molecular dynamics simulation studies showed that ivermectin may require homodimeric form of 3CLpro enzyme for its inhibitory activity. In summary, these molecules could be useful to develop highly specific therapeutically viable drugs to inhibit the SARS-CoV-2 replication either alone or in combination with drugs specific for other SARS-CoV-2 viral targets.

scholarly journals Screening of an FDA-Approved Library for Novel Drugs against Y. pestis

Antibiotics ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 40
Author(s):  
David Gur ◽  
Theodor Chitlaru ◽  
Emanuelle Mamroud ◽  
Ayelet Zauberman
Keyword(s):  
Drug Repurposing ◽  
Mortality Rates ◽  
Systematic Screening ◽  
Antibiotic Resistant ◽  
Gram Negative ◽  
Therapy Initiation ◽  
Novel Drugs ◽  
Resistant Strains ◽  
Approved Drugs ◽  
Fda Approved Drugs

Yersinia pestis is a Gram-negative pathogen that causes plague, a devastating disease that kills millions worldwide. Although plague is efficiently treatable by recommended antibiotics, the time of antibiotic therapy initiation is critical, as high mortality rates have been observed if treatment is delayed for longer than 24 h after symptom onset. To overcome the emergence of antibiotic resistant strains, we attempted a systematic screening of Food and Drug Administration (FDA)-approved drugs to identify alternative compounds which may possess antibacterial activity against Y. pestis. Here, we describe a drug-repurposing approach, which led to the identification of two antibiotic-like activities of the anticancer drugs bleomycin sulfate and streptozocin that have the potential for designing novel antiplague therapy approaches. The inhibitory characteristics of these two drugs were further addressed as well as their efficiency in affecting the growth of Y. pestis strains resistant to doxycycline and ciprofloxacin, antibiotics recommended for plague treatment.

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