Selective DNA Gyrase Inhibitors: Multi-Target In Silico Profiling with 3D-Pharmacophores

(1) Background: DNA gyrase is an important target for the development of novel antibiotics. Although ATP-competitive DNA gyrase (GyrB) inhibitors are a well-studied class of antibacterial agents, there is currently no representative used in therapy, largely due to unwanted off-target activities. Selectivity of GyrB inhibitors against closely related human ATP-binding enzymes should be evaluated early in development to avoid off-target binding to homologous binding domains. (2) Methods: To address this challenge, we developed selective 3D-pharmacophore models for GyrB, human topoisomerase IIα (TopoII), and the Hsp90 N-terminal domain (NTD) to be used in in silico activity profiling paradigms to identify molecules selective for GyrB over TopoII and Hsp90, as starting points for hit expansion and lead optimization. (3) Results: The models were used to profile highly active GyrB, TopoII, and Hsp90 inhibitors. Selected compounds were tested in in vitro assays. GyrB inhibitors 1 and 2 were inactive against TopoII and Hsp90, while 3 and 4, potent Hsp90 inhibitors, displayed no inhibition of GyrB and TopoII, and TopoII inhibitors 5 and 6 were inactive at GyrB and Hsp90. (4) Conclusions: The results provide a proof of concept for the use of target activity profiling methods to identify selective starting points for hit and lead identification.

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Taxifolin as dual inhibitor of Mtb DNA gyrase and isoleucyl-tRNA synthetase: in silico molecular docking, dynamics simulation and in vitro assays

In Silico Pharmacology ◽

10.1007/s40203-018-0045-5 ◽

2018 ◽

Vol 6 (1) ◽

Cited By ~ 4

Author(s):

Charles Kozhikkadan Davis ◽

K. Nasla ◽

A. K. Anjana ◽

G. K. Rajanikant

Keyword(s):

Molecular Docking ◽

In Silico ◽

Dna Gyrase ◽

Trna Synthetase ◽

Dynamics Simulation ◽

In Vitro Assays ◽

Dual Inhibitor ◽

In Silico Molecular Docking

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In vitro antimicrobial evaluation and in silico studies of coumarin derivatives tagged with pyrano-pyridine and pyrano-pyrimidine moieties as DNA gyrase inhibitors

Molecular Diversity ◽

10.1007/s11030-021-10224-4 ◽

2021 ◽

Author(s):

Eman A. Fayed ◽

Eman S. Nosseir ◽

Ahmed Atef ◽

Samar A. El‑Kalyoubi

Keyword(s):

In Silico ◽

Dna Gyrase ◽

Coumarin Derivatives ◽

In Silico Studies ◽

Antimicrobial Evaluation ◽

Gyrase Inhibitors

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In-silico Studies of Isolated Phytoalkaloid Against Lipoxygenase: Study Based on Possible Correlation

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207321666180220125406 ◽

2018 ◽

Vol 21 (3) ◽

pp. 215-221

Author(s):

Haroon Khan ◽

Muhammad Zafar ◽

Helena Den-Haan ◽

Horacio Perez-Sanchez ◽

Mohammad Amjad Kamal

Keyword(s):

In Silico ◽

Docking Studies ◽

In Vivo Studies ◽

In Vitro Assays ◽

Chronic Obstructive ◽

Lipoxygenase Inhibitors ◽

Lipoxygenase Inhibition ◽

In Silico Studies

Aim and Objective: Lipoxygenase (LOX) enzymes play an important role in the pathophysiology of several inflammatory and allergic diseases including bronchial asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, rheumatoid arthritis and chronic obstructive pulmonary disease. Inhibitors of the LOX are believed to be an ideal approach in the treatment of diseases caused by its over-expression. In this regard, several synthetic and natural agents are under investigation worldwide. Alkaloids are the most thoroughly investigated class of natural compounds with outstanding past in clinically useful drugs. In this article, we have discussed various alkaloids of plant origin that have already shown lipoxygenase inhibition in-vitro with possible correlation in in silico studies. Materials and Methods: Molecular docking studies were performed using MOE (Molecular Operating Environment) software. Among the ten reported LOX alkaloids inhibitors, derived from plant, compounds 4, 2, 3 and 1 showed excellent docking scores and receptor sensitivity. Result and Conclusion: These compounds already exhibited in vitro lipoxygenase inhibition and the MOE results strongly correlated with the experimental results. On the basis of these in vitro assays and computer aided results, we suggest that these compounds need further detail in vivo studies and clinical trial for the discovery of new more effective and safe lipoxygenase inhibitors. In conclusion, these results might be useful in the design of new and potential lipoxygenase (LOX) inhibitors.

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

Current Computer - Aided Drug Design ◽

10.2174/1386207323666200717155640 ◽

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.

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Computational and In-Vitro Validation of Natural Molecules as Potential Acetylcholinesterase Inhibitors and Neuroprotective Agents

Current Alzheimer Research ◽

10.2174/1567205016666181212155147 ◽

2019 ◽

Vol 16 (2) ◽

pp. 116-127 ◽

Cited By ~ 2

Author(s):

Ashwani Kumar ◽

Vineet Mehta ◽

Utkarsh Raj ◽

Pritish Kumar Varadwaj ◽

Malairaman Udayabanu ◽

...

Keyword(s):

In Silico ◽

Hippocampal Neurons ◽

Symptomatic Relief ◽

In Vitro Assays ◽

Disease Modifying Drugs ◽

In Silico Docking ◽

Ache Inhibitors ◽

Significant Difference ◽

Disease Modifying

Background: Cholinesterase inhibitors are the first line of therapy for the management of Alzheimer’s disease (AD), however, it is now established that they provide only temporary and symptomatic relief, besides, having several inherited side-effects. Therefore, an alternative drug discovery method is used to identify new and safer ‘disease-modifying drugs’. Methods: Herein, we screened 646 small molecules of natural origin having reported pharmacological and functional values through in-silico docking studies to predict safer neuromodulatory molecules with potential to modulate acetylcholine metabolism. Further, the potential of the predicted molecules to inhibit acetylcholinesterase (AChE) activity and their ability to protect neurons from degeneration was determined through in-vitro assays. Results: Based on in-silico AChE interaction studies, we predicted quercetin, caffeine, ascorbic acid and gallic acid to be potential AChE inhibitors. We confirmed the AChE inhibitory potential of these molecules through in-vitro AChE inhibition assay and compared results with donepezil and begacestat. Herbal molecules significantly inhibited enzyme activity and inhibition for quercetin and caffeine did not show any significant difference from donepezil. Further, the tested molecules did not show any neurotoxicity against primary (E18) hippocampal neurons. We observed that quercetin and caffeine significantly improved neuronal survival and efficiently protected hippocampal neurons from HgCl2 induced neurodegeneration, which other molecules, including donepezil and begacestat, failed to do. Conclusion: Quercetin and caffeine have the potential as “disease-modifying drugs” and may find application in the management of neurological disorders such as AD.

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Synthesis, Characterization and in vitro Antimicrobial Evaluation of Chalconeimine Derivatives as Potential Inhibitors against Enzymes Produced from S. aureus: A Computational Approach

Asian Journal of Chemistry ◽

10.14233/ajchem.2019.22028 ◽

2019 ◽

Vol 31 (10) ◽

pp. 2157-2164

Author(s):

B. Prithivirajan ◽

M. Jebastin Sonia Jas ◽

G. Marimuthu

Keyword(s):

Antibacterial Agents ◽

Dna Gyrase ◽

Bacterial Strains ◽

Bacterial Proteins ◽

Antibiotic Drug ◽

In Vitro Antibacterial Activity ◽

Antimicrobial Evaluation ◽

Potential Inhibitors ◽

Gyrase Inhibitors

(Z)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(4-(difluoromethoxy)-3-hydroxyphenyl)prop-2-en-1-one hydrazone derivatives pronounced in this manuscript represents a new collection of antibacterial agents in addition to the DNA gyrase inhibitors. Efforts had been made to synthesize those chalcone-hydrazone derivatives (4a-e) in good yields. The literature survey confirms that nano-ZnO as heterogeneous catalyst has obtained big interest because of its ecofriendly nature and has been explored as a effective catalyst for several organic ameliorations. Subsequently, induced by way of these observations and in continuation to our interest in organic synthesis with using nanocatalyst. in vitro Antibacterial activity has been evaluated towards Gram-positive and Gram-negative bacterial strains for all compounds. So one can discover the affinity to bacterial proteins docking have a look at have been carried out for 5 synthesized derivatives, antibiotic drug and co-crystallized ligands with special mechanism of action DNA gyrase B and methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) the usage of AutoDock 4.

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Prediction Mechanism of Nevadensin as Antibacterial Agent against S. sanguinis: In vitro and In silico Studies

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207324666210707104440 ◽

2021 ◽

Vol 24 ◽

Author(s):

Aldina Amalia Nur Shadrina ◽

Yetty Herdiyati ◽

Ika Wiani ◽

Mieke Hemiawati Satari ◽

Dikdik Kurnia

Keyword(s):

Antibacterial Activity ◽

Molecular Docking ◽

Dental Caries ◽

Binding Affinity ◽

In Silico ◽

Antibacterial Agent ◽

In Silico Analysis ◽

Dna Gyrase ◽

Silico Analysis

Background: Streptococcus sanguinis can contribute to tooth demineralization, which can lead to dental caries. Antibiotics used indefinitely to treat dental caries can lead to bacterial resistance. Discovering new antibacterial agents from natural products like Ocimum basilicum will help combat antibiotic resistance. In silico analysis (molecular docking) can help determine the lead compound by studying the molecular interaction between the drug and the target receptor (MurA enzyme and DNA gyrase). It is a potential candidate for antibacterial drug development. Objective: The research objective is to isolate the secondary metabolite of O. basilicum extract that has activity against S. sanguinis through in vitro and in silico analysis. Methods: n-Hexane extract of O. basilicum was purified by combining column chromatography with bioactivity-guided. The in vitro antibacterial activity against S. sanguinis was determined using the disc diffusion and microdilution method, while molecular docking simulation of nevadensin (1) with MurA enzyme and DNA gyrase was performed used PyRx 0.8 program. Results: Nevadensin from O. basilicum was successfully isolated and characterized by spectroscopic methods. This compound showed antibacterial activity against S. sanguinis with MIC and MBC values of 3750 and 15000 μg/mL, respectively. In silico analysis showed that the binding affinity to MurA was -8.5 Kcal/mol, and the binding affinity to DNA gyrase was -6.7 Kcal/mol. The binding of nevadensin-MurA is greater than fosfomycin-MurA. Otherwise, Nevadensin-DNA gyrase has a weaker binding affinity than fluoroquinolone-DNA gyrase and chlorhexidine-DNA gyrase. Conclusion: Nevadensin showed potential as a new natural antibacterial agent by inhibiting the MurA enzyme rather than DNA gyrase.

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Computational Chemogenomics Drug Repositioning Strategy Enables the Discovery of Epirubicin as a New Repurposed Hit for Plasmodium falciparum and P. vivax

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02041-19 ◽

2020 ◽

Vol 64 (9) ◽

Author(s):

Letícia Tiburcio Ferreira ◽

Juliana Rodrigues ◽

Gustavo Capatti Cassiano ◽

Tatyana Almeida Tavella ◽

Kaira Cristina Peralis Tomaz ◽

...

Keyword(s):

Plasmodium Falciparum ◽

In Silico ◽

Antimalarial Activity ◽

Drug Repositioning ◽

Dna Gyrase ◽

Plasmodium Yoelii ◽

Computer Assisted ◽

Content Type

ABSTRACT Widespread resistance against antimalarial drugs thwarts current efforts for controlling the disease and urges the discovery of new effective treatments. Drug repositioning is increasingly becoming an attractive strategy since it can reduce costs, risks, and time-to-market. Herein, we have used this strategy to identify novel antimalarial hits. We used a comparative in silico chemogenomics approach to select Plasmodium falciparum and Plasmodium vivax proteins as potential drug targets and analyzed them using a computer-assisted drug repositioning pipeline to identify approved drugs with potential antimalarial activity. Among the seven drugs identified as promising antimalarial candidates, the anthracycline epirubicin was selected for further experimental validation. Epirubicin was shown to be potent in vitro against sensitive and multidrug-resistant P. falciparum strains and P. vivax field isolates in the nanomolar range, as well as being effective against an in vivo murine model of Plasmodium yoelii. Transmission-blocking activity was observed for epirubicin in vitro and in vivo. Finally, using yeast-based haploinsufficiency chemical genomic profiling, we aimed to get insights into the mechanism of action of epirubicin. Beyond the target predicted in silico (a DNA gyrase in the apicoplast), functional assays suggested a GlcNac-1-P-transferase (GPT) enzyme as a potential target. Docking calculations predicted the binding mode of epirubicin with DNA gyrase and GPT proteins. Epirubicin is originally an antitumoral agent and presents associated toxicity. However, its antiplasmodial activity against not only P. falciparum but also P. vivax in different stages of the parasite life cycle supports the use of this drug as a scaffold for hit-to-lead optimization in malaria drug discovery.

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[18F]Amylovis as a Potential PET Probe for β-Amyloid Plaque: Synthesis, In Silico, In vitro and In vivo Evaluations

Current Radiopharmaceuticals ◽

10.2174/1874471012666190102165053 ◽

2019 ◽

Vol 12 (1) ◽

pp. 58-71 ◽

Cited By ~ 2

Author(s):

Suchitil Rivera-Marrero ◽

Laura Fernández-Maza ◽

Samila León-Chaviano ◽

Marquiza Sablón-Carrazana ◽

Alberto Bencomo-Martínez ◽

...

Keyword(s):

In Silico ◽

Specific Activity ◽

Senile Plaques ◽

Coupling Reaction ◽

In Vitro Assays ◽

Mice Model ◽

Wild Mice ◽

In Silico Studies

Background: Alzheimer’s disease (AD) is the most common form of dementia. Neuroimaging methods have widened the horizons for AD diagnosis and therapy. The goals of this work are the synthesis of 2-(3-fluoropropyl)-6-methoxynaphthalene (5) and its [18F]-radiolabeled counterpart ([18F]Amylovis), the in silico and in vitro comparative evaluations of [18F]Amylovis and [11C]Pittsburg compound B (PIB) and the in vivo preclinical evaluation of [18F]Amylovis in transgenic and wild mice. Methods: Iron-catalysis cross coupling reaction, followed by fluorination and radiofluorination steps were carried out to obtain 5 and 18F-Amylovis. Protein/Aß plaques binding, biodistribution, PET/CT Imaging and immunohistochemical studies were conducted in healthy/transgenic mice. Results: The synthesis of 5 was successful obtained. Comparative in silico studies predicting that 5 should have affinity to the Aβ-peptide, mainly through π-π interactions. According to a dynamic simulation study the ligand-Aβ peptide complexes are stable in simulation-time (ΔG = -5.31 kcal/mol). [18F]Amylovis was obtained with satisfactory yield, high radiochemical purity and specific activity. The [18F]Amylovis log Poct/PBS value suggests its potential ability for crossing the blood brain barrier (BBB). According to in vitro assays, [18F]Amylovis has an adequate stability in time. Higher affinity to Aβ plaques were found for [18F]Amylovis (Kd 0.16 nmol/L) than PIB (Kd 8.86 nmol/L) in brain serial sections of 3xTg-AD mice. Biodistribution in healthy mice showed that [18F]Amylovis crosses the BBB with rapid uptake (7 %ID/g at 5 min) and good washout (0.11±0.03 %ID/g at 60 min). Comparative PET dynamic studies of [18F]Amylovis in healthy and transgenic APPSwe/PS1dE9 mice, revealed a significant high uptake in the mice model. Conclusion: The in silico, in vitro and in vivo results justify that [18F]Amylovis should be studied as a promissory PET imaging agent to detect the presence of Aβ senile plaques.

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