Identifying potential natural inhibitors of Brucella melitensis Methionyl-tRNA synthetase through an in-silico approach

AbstractBackgroundBrucellosis is an infectious disease caused by bacteria of the genus Brucella. Although it is the most common zoonosis worldwide, there are increasing reports of drug resistance and cases of relapse after long term treatment with the existing drugs of choice. This study therefore aims at identifying possible natural inhibitors of Brucella melitensis Methionyl-tRNA synthetase through an in-silico approach.MethodsUsing PyRx 0.8 virtual screening software, the target was docked against a library of natural compounds obtained from edible African plants. The compound, 2-({3-[(3,5-dichlorobenzyl) amino] propyl} amino) quinolin-4(1H)-one (OOU) which is a co-crystallized ligand with the target was used as the reference compound. Screening of the molecular descriptors of the compounds for bioavailability, pharmacokinetic properties, and bioactivity was performed using the SWISSADME, pkCSM, and Molinspiration web servers respectively. The Fpocket and PLIP webservers were used to perform the analyses of the binding pockets and the protein ligand interactions. Analysis of the time-resolved trajectories of the Apo and Holo forms of the target was performed using the Galaxy and MDWeb servers. The lead compounds, Strophanthidin and Isopteropodin are present in Corchorus olitorius and Uncaria tomentosa (cat-claw) plants respectively.ResultsIsopteropodin had a binding affinity score of -8.9 kcal / ml with the target and had 17 anti-correlating residues in pocket 1 after molecular dynamics simulation. The complex formed by Isopteropodin and the target had a total RMSD of 4.408 and a total RMSF of 9.8067. However, Strophanthidin formed 3 hydrogen bonds with the target at ILE21, GLY262 and LEU294, and induced a total RMSF of 5.4541 at Pocket 1.ConclusionOverall, Isopteropodin and Strophanthidin were found to be better drug candidates than OOU and they showed potentials to inhibit the Brucella melitensis Methionyl-tRNA synthetase at Pocket 1, hence abilities to treat brucellosis. In vivo and in vitro investigations are needed to further evaluate the efficacy and toxicity of the lead compounds.Author SummaryStrophanthidin and Isopteropodin showed potentials to inhibit the Brucella melitensis Methionyl-tRNA synthetase at Pocket 1Both compounds can be used to treat brucellosis.Both compounds showed potentials of being safe to use in humans.

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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 evaluation and molecular dynamics, DFT guided investigation of antimalarial activity of ethnomedicinally used Coptis teeta Wall

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207324666210118095503 ◽

2021 ◽

Vol 24 ◽

Author(s):

Ashis Kumar Goswami ◽

Hemanta Kumar Sharma ◽

Neelutpal Gogoi ◽

Ankita Kashyap ◽

Bhaskar Jyoti Gogoi

Keyword(s):

Molecular Dynamics ◽

In Silico ◽

Density Functional ◽

Antimalarial Activity ◽

In Silico Analysis ◽

Dynamics Simulation ◽

Discovery Studio ◽

North East ◽

Silico Analysis

Background: Malaria is caused by different species of Plasmodium; among which P. falciparum is the most severe. Coptis teeta is an ethnomedicinal plant of enormous importance for tribes of north east India. Objective: In this study, the anti malarial activity of the methanol extracts of Coptis teeta was evaluated in vitro and lead identification via in silico study. Method: On the basis of the in vitro results, in silico analysis by application of different modules of Discovery Studio 2018 was performed on multiple targets of P. falciparum taking into consideration some of the compounds reported from C. teeta. Results: The IC50 of the methanol extract of Coptis teeta 0.08 µg/ml in 3D7 strain and 0.7 µg/ml in Dd2 strain of P. falciparum. From the docking study, noroxyhydrastatine was observed to have better binding affinity in comparison to chloroquine. The binding of noroxyhydrastinine with dihydroorotate dehydrogenase was further validated by molecular dynamics simulation and was observed to be significantly stable in comparison to the co-crystal inhibitor. During simulations it was observed that noroxyhydrastinine retained the interactions, giving strong indications of its effectiveness against the P. falciparum proteins and stability in the binding pocket. From the Density-functional theory analysis, the band gap energy of noroxyhydrastinine was found to be 0.186 Ha indicating a favourable interaction. Conclusion: The in silico analysis as an addition to the in vitro results provide strong evidence of noroxyhydrastinine as an anti malarial agent.

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Methionyl-tRNA synthetase inhibitor has potent in vivo activity in a novel Giardia lamblia luciferase murine infection model

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz567 ◽

2020 ◽

Vol 75 (5) ◽

pp. 1218-1227

Author(s):

Samantha A Michaels ◽

Han-Wei Shih ◽

Bailin Zhang ◽

Edelmar D Navaluna ◽

Zhongsheng Zhang ◽

...

Keyword(s):

Giardia Lamblia ◽

Trna Synthetase ◽

Luciferase Reporter ◽

Infection Model ◽

Cell Assay ◽

Mouse Infection Model ◽

Mouse Infection ◽

Methionyl Trna Synthetase

Abstract Background Methionyl-tRNA synthetase (MetRS) inhibitors are under investigation for the treatment of intestinal infections caused by Giardia lamblia. Objectives To properly analyse the therapeutic potential of the MetRS inhibitor 1717, experimental tools including a robust cell-based assay and a murine model of infection were developed based on novel strains of G. lamblia that employ luciferase reporter systems to quantify viable parasites. Methods Systematic screening of Giardia-specific promoters and luciferase variants led to the development of a strain expressing the click beetle green luciferase. Further modifying this strain to express NanoLuc created a dual reporter strain capable of quantifying parasites in both the trophozoite and cyst stages. These strains were used to develop a high-throughput cell assay and a mouse infection model. A library of MetRS inhibitors was screened in the cell assay and Compound-1717 was tested for efficacy in the mouse infection model. Results Cell viability in in vitro compound screens was quantified via bioluminescence readouts while infection loads in mice were monitored with non-invasive whole-animal imaging and faecal analysis. Compound-1717 was effective in clearing mice of Giardia infection in 3 days at varying doses, which was supported by data from enzymatic and phenotypic cell assays. Conclusions The new in vitro and in vivo assays based on luciferase expression by engineered G. lamblia strains are useful for the discovery and development of new therapeutics for giardiasis. MetRS inhibitors, as validated by Compound-1717, have promising anti-giardiasis properties that merit further study as alternative therapeutics.

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Genetic engineering of methionyl-tRNA synthetase: in vitro regeneration of an active synthetase by proteolytic cleavage of a methionyl-tRNA synthetase-β-galactosidase chimeric protein

Biochimie ◽

10.1016/0300-9084(88)90107-1 ◽

1988 ◽

Vol 70 (6) ◽

pp. 773-782 ◽

Cited By ~ 36

Author(s):

P.-Hervé Hirel ◽

Françoise Lévêque ◽

Patrice Mellot ◽

Frédéric Dardel ◽

Michel Panvert ◽

...

Keyword(s):

Genetic Engineering ◽

In Vitro Regeneration ◽

Chimeric Protein ◽

Proteolytic Cleavage ◽

Trna Synthetase ◽

Methionyl Trna Synthetase

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Astaxanthin-Mediated Bacterial Lethality: Evidence from Oxidative Stress Contribution and Molecular Dynamics Simulation

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/7159652 ◽

2021 ◽

Vol 2021 ◽

pp. 1-24

Author(s):

Jamiu Olaseni Aribisala ◽

Sonto Nkosi ◽

Kehinde Idowu ◽

Ismaila Olanrewaju Nurain ◽

Gaositwe Melvin Makolomakwa ◽

...

Keyword(s):

Oxidative Stress ◽

In Silico ◽

Current Knowledge ◽

Dynamics Simulation ◽

The Novel ◽

Topoisomerase Iv ◽

Test Organisms ◽

Gyrase A ◽

Vitro Analysis

The involvement of cellular oxidative stress in antibacterial therapy has remained a topical issue over the years. In this study, the contribution of oxidative stress to astaxanthin-mediated bacterial lethality was evaluated in silico and in vitro. For the in vitro analysis, the minimum inhibitory concentration (MIC) of astaxanthin was lower than that of novobiocin against Staphylococcus aureus but generally higher than those of the reference antibiotics against other test organisms. The level of superoxide anion of the tested organisms increased significantly following treatment with astaxanthin when compared with DMSO-treated cells. This increase compared favorably with those observed with the reference antibiotics and was consistent with a decrease in the concentration of glutathione (GSH) and corresponding significant increase in ADP/ATP ratio. These observations are suggestive of probable involvement of oxidative stress in antibacterial capability of astaxanthin and in agreement with the results of the in silico evaluations, where the free energy scores of astaxanthins’ complexes with topoisomerase IV ParC and ParE were higher than those of the reference antibiotics. These observations were consistent with the structural stability and compactness of the complexes as astaxanthin was observed to be more stable against topoisomerase IV ParC and ParE than DNA Gyrase A and B. Put together, findings from this study underscored the nature and mechanism of antibacterial action of astaxanthin that could suggest practical approaches in enhancing our current knowledge of antibacterial arsenal and aid in the novel development of alternative natural topo2A inhibitor.

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Dual targeting of cytokine storm and viral replication in COVID-19 by plant-derived steroidal pregnanes in silico

10.21203/rs.3.rs-329239/v1 ◽

2021 ◽

Author(s):

Gideon A. Gyebi ◽

Oludare M. Ogunyemi ◽

Ibrahim M. Ibrahim ◽

Saheed O. Afolabi ◽

Joseph O. Adebayo

Keyword(s):

In Silico ◽

Glucocorticoid Receptors ◽

Active Regions ◽

Binding Energies ◽

Dynamics Simulation ◽

Mode Analysis ◽

High Morbidity ◽

Cytokine Storm

Abstract The high morbidity and mortality rate of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection arises majorly from the Acute Respiratory Distress Syndrome and “cytokine storm” syndrome, which is sustained by an aberrant systemic inflammatory response and elevated pro-inflammatory cytokines. Thus, phytocompounds with broad-spectrum anti-inflammatory activity that target multiple SARS-CoV-2 proteins will enhance the development of effective drugs against the disease. In this study, an in-house library of 106 steriodal plant-derived pregnanes (PDPs) was docked in the active regions of human glucocorticoid receptors (hGRs) in a comparative molecular docking analysis. Based on the minimal binding energy and a comparative dexamethason binding mode analysis, a list of top twenty ranked PDPs docked in the agonist conformation of hGR, with binding energies ranging between -9.8 and -11.2 Kcal/mol, was obtained and analyzed for interactions with the human Janus kinases 1 and Interleukins-6 and SARS-CoV-2 3-chymotrypsin-like protease, Papain-like protease and RNA-dependent RNA polymerase. For each target protein, the top three ranked PDPs were selected. Eight PDPs (bregenin, hirundigenin, anhydroholantogenin, atratogenin A, atratogenin B, glaucogenin A, glaucogenin C and glaucogenin D) with high binding tendencies to the catalytic residues of multiple targets were identified. A high degree of structural stability was observed from the 100 ns molecular dynamics simulation analyses of glaucogenin C and hirundigenin complexes of hGR. The selected top-eight ranked PDPs demonstrated favourable druggable and in silico ADMET properties. Thus, the therapeutic potentials of glaucogenin C and hirundigenin can be explored for further in vitro and in vivo studies.

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3-Oxoacyl-ACP Reductase from Schistosoma japonicum: Integrated In Silico-In Vitro Strategy for Discovering Antischistosomal Lead Compounds

PLoS ONE ◽

10.1371/journal.pone.0064984 ◽

2013 ◽

Vol 8 (6) ◽

pp. e64984 ◽

Cited By ~ 12

Author(s):

Jian Liu ◽

Dave Dyer ◽

Jipeng Wang ◽

Shuqi Wang ◽

Xiaofeng Du ◽

...

Keyword(s):

Schistosoma Japonicum ◽

In Silico ◽

Lead Compounds

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Luteolin and abyssinone II as potential inhibitors of SARS-CoV-2: an in silico molecular modeling approach in battling the COVID-19 outbreak

Bulletin of the National Research Centre ◽

10.1186/s42269-020-00479-6 ◽

2021 ◽

Vol 45 (1) ◽

Author(s):

Mohammad Mahfuz Ali Khan Shawan ◽

Sajal Kumar Halder ◽

Md. Ashraful Hasan

Keyword(s):

Molecular Dynamics ◽

Root Mean Square ◽

In Silico ◽

Binding Free Energy ◽

Biologically Active ◽

Dynamics Simulation ◽

Mean Square ◽

Efficient Treatment ◽

Target Proteins

Abstract Background At present, the entire world is in a war against COVID-19 pandemic which has gradually led us toward a more compromised “new normal” life. SARS-CoV-2, the pathogenic microorganism liable for the recent COVID-19 outbreak, is extremely contagious in nature resulting in an unusual number of infections and death globally. The lack of clinically proven therapeutic intervention for COVID-19 has dragged the world’s healthcare system into the biggest challenge. Therefore, development of an efficient treatment scheme is now in great demand. Screening of different biologically active plant-based natural compounds could be a useful strategy for combating this pandemic. In the present research, a collection of 43 flavonoids of 7 different classes with previously recorded antiviral activity was evaluated via computational and bioinformatics tools for their impeding capacity against SARS-CoV-2. In silico drug likeness, pharmacophore and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) profile analysis of the finest ligands were carried out using DataWarrior, DruLiTo and admetSAR programs, respectively. Molecular docking was executed by AutoDock Vina, while molecular dynamics simulation of the target protein–ligand bound complexes was done using nanoscalable molecular dynamics and visual molecular dynamics software package. Finally, the molecular target analysis of the selected ligands within Homo sapiens was conducted with SwissTargetPredcition web server. Results Out of the forty-three flavonoids, luteolin and abyssinone II were found to develop successful docked complex within the binding sites of target proteins in terms of lowest binding free energy and inhibition constant. The root mean square deviation and root mean square fluctuation values of the docked complex displayed stable interaction and efficient binding between the ligands and target proteins. Both of the flavonoids were found to be safe for human use and possessed good drug likeness properties and target accuracy. Conclusions Conclusively, the current study proposes that luteolin and abyssinone II might act as potential therapeutic candidates for SARS-CoV-2 infection. In vivo and in vitro experiments, however, should be taken under consideration to determine the efficiency and to demonstrate the mechanism of action.

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Bioactivity guided extraction of PDHC [3,3’-(propane-2,2-diyl)bis(3,4,5,6,7,8- hexahydro-1h-isochromene)]: A Novel antibacterial compound from an ornamental plant Polyalthia longifolia

Research Journal of Pharmacy and Technology ◽

10.52711/0974-360x.2021.00372 ◽

2021 ◽

pp. 2101-2107

Author(s):

Gayathri Segaran ◽

Lokesh Ravi ◽

Mythili Sathiavelu

Keyword(s):

Antibacterial Activity ◽

In Silico ◽

Antibacterial Effect ◽

Docking Studies ◽

Trna Synthetase ◽

Resistant Bacteria ◽

In Silico Docking ◽

Antibacterial Assay ◽

Polyalthia Longifolia

Objective: The objective of the study was to determine and compare the antibacterial effect of different ornamental plants and to isolate the effective bioactive compound with antibacterial activity from Polyalthia longifolia. Methods: Petroleum ether and methanol extracts of Bougainvillea glabra, Polyalthia longifolia, Ixora coccinea Linn. ,Plumeria rubra and Euphorbia milli leaves were investigated for antimicrobial activity by performing agar well difusion method. The plant extract with the highest antibacterial activity was selected and further used for the isolation of antibacterial compounds. In silico docking studies and in vitro antibacterial assay was performed to analyze the biological activity of pure compound. Results: The highest antibacterial activity was found in the pet ether of Polyalthia longifolia against all the tested bacterial strains and the extract was further selected for compound separation. A novel compound 3,3’-(propane-2,2-diyl)bis(3,4,5,6,7,8-hexahydro-1H-isochromene) (PHDC) with a molecular weight of 316.35 g/mol and molecular formula C21H32O2 was identified from Polyalthia longifolia by using spectroscopic studies. In the in vitro antibacterial assay, PHDC demonstrated significant antibacterial showed against Protease mirabilis. In silico docking studies revealed that PHDC showed antibacterial activity by inhibiting tRNA Synthetase (IleRS). PHDC exhibited the lowest binding energy of - 8.7Kcal/Mol for Isoleucyl tRNA Synthetase (IleRS), the protein responsible for protein synthesis. Conclusion: The emergence of multiple antibiotics resistant microbes has become huge nowadays and the infections caused by these resistant microbes cannot be treated with antibiotics. PHDC is a novel compound extracted from Polyalthia longifolia showed significant antibacterial effect and we suggest that the compound can be further used as lead molecules to overcome the infections caused by antibiotic resistant bacteria.

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