Exploration of the binding affinities between ecdysone agonists and EcR/USP by docking and MM-PB/GBSA approaches

Hu, Xueping; Xie, Jin; Hu, Song; Zhang, Li; Dong, Yanhong

doi:10.1007/s00894-017-3329-5

Cited by 8 publications

(6 citation statements)

References 43 publications

(45 reference statements)

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“…Models of the honeybee and Varroa Octβ2R-LBD were built using the Molecular Operating Environments (MOE, 2015.10) using the β2-adrenergic receptor and carazolol-bond crystal structures (PDB ID: 5D5A) as homology templates as described (Hu et al, 2017). The models were evaluated using Ramachandran plots and the UCLA-DOE server.…”

Section: Molecular Dockingmentioning

confidence: 99%

An octopamine receptor confers selective toxicity of amitraz on honeybees and Varroa mites

Guo

Fan

Qiao

et al. 2021

eLife

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The Varroa destructor mite is a devastating parasite of Apis mellifera honeybees. They can cause colonies to collapse by spreading viruses and feeding on the fat reserves of adults and larvae. Amitraz is used to control mites due to its low toxicity to bees; however, the mechanism of bee resistance to amitraz remains unknown. In this study, we found that amitraz and its major metabolite potently activated all four mite octopamine receptors. Behavioral assays using Drosophila null mutants of octopamine receptors identified one receptor subtype Octβ2R as the sole target of amitraz in vivo. We found that thermogenetic activation of octβ2R-expressing neurons mimics amitraz poisoning symptoms in target pests. We next confirmed that the mite Octβ2R was more sensitive to amitraz and its metabolite than the bee Octβ2R in pharmacological assays and transgenic flies. Furthermore, replacement of three bee-specific residues with the counterparts in the mite receptor increased amitraz sensitivity of the bee Octβ2R, indicating that relative insensitivity of their receptor is the major mechanism for honeybees to resist amitraz. The present findings have important implications for resistance management and the design of safer insecticides that selectively target pests while maintaining low toxicity to non-target pollinators.

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Section: Molecular Dockingmentioning

confidence: 99%

An octopamine receptor confers selective toxicity of amitraz on honeybees and Varroa mites

Guo

Fan

Qiao

et al. 2021

eLife

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“…Finally, the binding free energy was calculated for each protein ligand complex. In addition, Poisson-Boltzmann surface area continuum solvation (MM/PBSA) (Fu et al, 2018;Hu et al, 2017;Kumari et al, 2014;Moesgaard et al, 2020;Xue et al, 2018) was also performed to calculate the free binding energy of the ligand. Distance of 3.2 Å was kept as cutoff for bond length for salt bridge and hydrogen bond interactions (Mohammad et al, 2020;.…”

Section: Simulations Analysismentioning

confidence: 99%

Identification of potential inhibitors of SARS-COV-2 endoribonuclease (EndoU) from FDA approved drugs: a drug repurposing approach to find therapeutics for COVID-19

Chandra

Gurjar²,

Qamar

et al. 2020

Journal of Biomolecular Structure and Dynamics

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SARS-CoV-2 is causative agent of COVID-19, which is responsible for severe social and economic disruption globally. Lack of vaccine or antiviral drug with clinical efficacy suggested that drug repurposing approach may provide a quick therapeutic solution to COVID-19. Nonstructural protein-15 (NSP15) encodes for an uridylate-specific endoribonuclease (EndoU) enzyme, essential for virus life cycle and an attractive target for drug development. We have performed in silico based virtual screening of FDA approved compounds targeting EndoU in search of COVID-19 drugs from commercially available approved molecules. Two drugs Glisoxepide and Idarubicin used for treatment for diabetes and leukemia, respectively, were selected as stronger binder of EndoU. Both the drugs bound to the active site of the viral endonuclease by forming attractive intermolecular interactions with catalytically essential amino acid residues, His235, His250, and Lys290. Molecular dynamics simulation studies showed stable conformation dynamics upon drugs binding to endoU. The binding free energies for Glisoxepide and Idarubicin were calculated to be-141 ± 11 and-136 ± 16 kJ/mol, respectively. The IC 50 were predicted to be 9.2 mM and 30 mM for Glisoxepide and Idarubicin, respectively. Comparative structural analysis showed the stronger binding of EndoU to Glisoxepide and Idarubicin than to uridine monophosphate (UMP). Surface area calculations showed buried are of 361.8Å 2 by Glisoxepide which is almost double of the area occupied by UMP suggesting stronger binding of the drug than the ribonucleotide. However, further studies on these drugs for evaluation of their clinical efficacy and dose formulations may be required, which may provide a quick therapeutic option to treat COVID-19.

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“…The overall time of simulation was 20 ns, time necessary for ligand stabilization inside the binding cleft. Indeed, 10-20 ns is the average time needed for the ligand to reorient itself inside the pocket prior its dynamical evolution [58][59][60] . In fact, as it results from RMSD graphs (see Supplementary Information), all the ligand-protein complexes reach a steady state (average deviation RMSD=0.37±0.02) starting from an initial different orientation thus supporting that 10-20 ns is a reasonable time in this case.…”

Section: Ensemble Docking Via High Throughput Virtual Screening (Htvs...mentioning

confidence: 99%

Natural Alkaloid Berberine Activity against Pseudomonas aeruginosa MexXY-Mediated Aminoglycoside Resistance: In Silico and in Vitro Studies

et al. 2019

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The multidrug efflux system MexXY-OprM, inside the resistance-nodulation-division (RND) family, is a major determinant of aminoglycoside resistance in Pseudomonas aeruginosa. In the fight aimed to identify potential efflux pumps inhibitors (EPIs) among natural compounds, the alkaloid berberine emerged as a putative inhibitor of MexXY-OprM. In this work, we elucidated its interaction with the extrusor protein MexY and assessed its synergistic activity with aminoglycosides. In particular, we built an in silico model for the MexY protein in its trimeric association using both AcrB (E. coli) and MexB (P. aeruginosa) as 3D templates. This model has been stabilized in the bacterial cytoplasmic membrane using a molecular dynamics approach and used for ensemble docking to obtain the binding site mapping. Then, through dynamic docking, we assessed its binding affinity and its synergism with aminoglycosides focusing on tobramycin, which is widely used in the treatment of pulmonary infections. In vitro assays validated the data obtained: the results showed a two-fold increase of the inhibitory activity and 2-4 log increase of the killing activity of the association berberine-tobramycin compared to those of tobramycin alone against 13/28 tested P. aeruginosa clinical isolates. From hemolytic assays, we preliminary assessed berberine low toxicity.

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Exploration of the binding affinities between ecdysone agonists and EcR/USP by docking and MM-PB/GBSA approaches

Cited by 8 publications

References 43 publications

An octopamine receptor confers selective toxicity of amitraz on honeybees and Varroa mites

An octopamine receptor confers selective toxicity of amitraz on honeybees and Varroa mites

Identification of potential inhibitors of SARS-COV-2 endoribonuclease (EndoU) from FDA approved drugs: a drug repurposing approach to find therapeutics for COVID-19

Natural Alkaloid Berberine Activity against Pseudomonas aeruginosa MexXY-Mediated Aminoglycoside Resistance: In Silico and in Vitro Studies

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