Computational and Experimental Assessments of Magnolol as a Neuroprotective Agent and Utilization of UiO-66(Zr) as Its Drug Delivery System

Santos, J. H. M.; Quimque, Mark Tristan J.; Liman, Rhenz Alfred D.; Agbay, Jay Carl M.; Macabeo, Allan Patrick G.; Corpuz, Mary Jho Anne T.; Wang, Yun Ming; Lu, Tsai‐Te; Lin, Chia Her; Villaflores, Oliver B.

doi:10.1021/acsomega.1c02555

Cited by 20 publications

(22 citation statements)

References 73 publications

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“…The docking protocol was validated by re-docking bound co-crystallized ligand following the same protocol described above. The RMSD between the co-crystallized and re-docked ligand for the proteins was found to be less than 2 Å (ranging from 0.36-1.69 Å), which signifies that computed ligand-protein conformation is good (Acharya et al 2019;Santos et al 2021).…”

Section: Biological Assaysmentioning

confidence: 92%

Antituberculosis and Antiproliferative Activities of the Extracts and Tetrahydrobisbenzylisoquinoline Alkaloids from Phaeanthus ophthalmicus: In Vitro and In Silico Investigations

Malaluan¹,

Manzano²,

Muñoz³

et al. 2021

Philipp J Sci

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Tuberculosis (TB) and cancer are among the maladies with high morbidity and mortality rates to date. This prompted the utilization of natural products in the discovery and development of new anti-TB and anticancer derivatives. In this study, we explored the antitubercular and antiproliferative activities of extracts and tetrahydrobisbenzylisoquinoline alkaloids tetrandrine (1) and limacusine (2) from the Philippine medicinal plant Phaeanthus ophthalmicus. Antitubercular evaluation using colorimetric MABA (microplate Alamar blue assay) assays revealed antitubercular activities of the extracts and fractions [minimum inhibitory concentration (MIC) = 15.6 to < 64 μg/mL]. Among the two isolated alkaloids, limacusine (2) exhibited inhibitory activity against Mycobacterium tuberculosis (MIC = 42.6 μg/ml). In addition, CellTiter-Blue cell viability assay showed antiproliferative activity for limacusine (2) against K-562. Both tetrahydrobisbenzylisoquinoline alkaloids exhibited cytotoxicity on HeLa cells. To probe the binding mechanisms of 1 and 2 against putative protein targets, molecular docking simulations were carried out. Limacusine (2) showed high binding propensities to mycobacterial enzymes ATP-dependent murE ligase and enoyl acyl carrier protein reductase, thus illustrating possibilities of cell wall and mycolic biosynthesis inhibitory mechanisms, respectively. High binding affinity was also observed in 2 vs. FLT3, a protein target implicated in myeloid leukemia cell proliferation. Additionally, the limacusine-InhA and limacusine-FLT3 complexes were found to be dynamically stable as per molecular dynamics (MD) simulations. The results of in vitro

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Section: Biological Assaysmentioning

confidence: 92%

Antituberculosis and Antiproliferative Activities of the Extracts and Tetrahydrobisbenzylisoquinoline Alkaloids from Phaeanthus ophthalmicus: In Vitro and In Silico Investigations

Malaluan¹,

Manzano²,

Muñoz³

et al. 2021

Philipp J Sci

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“…After equilibration, a total of 50 ns simulation was performed for each system at a constant temperature of 300 K. The dynamic trajectories were recorded during the simulation at every 10 ps. These trajectories were then used for the analysis of the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) (de Leon et al 2021;Santos et al 2021).…”

Section: Molecular Docking Studiesmentioning

confidence: 99%

“…All six top-ranking compounds (1, 2, 3, 4, 5, and 6) showed a tight and compact binding with the aromatase catalytic site. The low differences between the highest and lowest radii per compound indicate relatively tight and stable compaction of the aromatase secondary structures in a complex with a phytochemical (Quimque et al 2020b;Santos et al 2021).…”

Section: Location Type Of Interaction Key Amino Acidsmentioning

confidence: 99%

In Silico Potentials of Alpinia galanga Constituents against Human Placental Aromatase Vital in Postmenopausal Estrogen-dependent Breast Cancer Pathogenesis

Manzano¹,

Cruz²,

Quimque³

et al. 2022

Philipp J Sci

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Breast cancer is the leading cause of cancer-related deaths among women. With the clinical success of several synthetic aromatase inhibitors (AIs) as therapeutic agents in post-menopausal estrogen receptor-positive breast cancer, natural products have been tapped in search of chemically diverse compounds with potential better effectiveness against aromatase while conferring reduced adverse effects. Alpinia galanga is among the Philippine native medicinal plants with extensive studies on its phytopharmacological properties, yet reports on its human placental aromatase inhibitory activity remain rudimentary. To determine the aromatase inhibitory activity of A. galanga in silico, a total of 119 database-derived A. galanga secondary metabolites were evaluated molecularly docked onto the catalytic site of human placental aromatase using the UCSF Chimera platforms according to the AutoDock Vina BFGS algorithm. To assess binding stability, molecular dynamics (MD) simulations using the GROMACS software package were carried out. Drug-likeness was assessed in silico using SwissADME. Of the screened compounds, galanolactone (1), 4-(3,4-dimethoxy-trans-cinnamoyl)-trans-cinnamic acid (2), isocoronarin D (3), quercetin (4), β-sitosterol (5), (E)-8ß,17-epoxylabd-12-ene-15,16-dial (6), galangin (7), labda- 8(17),12-diene-15,16-dial (8), 7-(4-Hydroxy-3-methoxyphenyl)-1-phenylhept-4-en-3-one (9), and 3,5,7-trihydroxy-4-methoxyflavanone (10) conferred highest binding affinities against aromatase ranging from binding energies of –8.7 to –8.0 kcal/mol with notable formed hydrogen bonds and interactions against key amino acid residues. Top-ranked compounds were predicted to have good druggability, whereas MD simulations demonstrated the stability of the ligands inside the complex. Overall, the study indicates the potential of top A. galanga secondary metabolites as promising drug pharmacophores in developing therapeutics against breast cancer.

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“…Visualization and analysis of the enzyme−ligand complex conformation were carried out using ChimeraX and Biovia Discovery Studios (version 4.1) (Quimque et al, 2021). Validation of the docking protocol was done by extracting the bound co-crystallized ligand and re-docking it to the set grid (Quimque et al, 2021;Santos et al, 2021).…”

Section: Molecular Dockingmentioning

confidence: 99%

Flavonoids from Uvaria alba attenuate LPS-induced inflammatory responses by suppressing NF-κB activation in RAW 264.7 macrophages: In silico and in vitro perspectives

Notarte

Quimque

Macaranas

et al. 2022

Preprint

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Hyperreactive inflammatory response occurs when there is excessive activation of NF-κB leading to a pathologic cascade of inflammatory reactions. Thus, we investigated the inflammatory modulating potentials of the Philippine medicinal endemic plant Uvaria alba. ELISA was initially performed to measure levels of proinflammatory mediators (NO and PGE 2 ) and cytokines (TNF-α, IL-1β and IL-6), followed by RT-PCR and western blotting to determine mRNA and protein expression, respectively. Using immunofluorescence staining combined with western blot analysis, the activation of NF-κB was further investigated. Putative flavonoids from the bioactive butanol subextract (UaB) were identified using high resolution LC-MS and subjected to in silico screening against COX-1/2, iNOS, TNF-α, TACE, and IKK via molecular docking and molecular dynamics simulations at 140 ns. UaB abrogated protein and mRNA expressions of iNOS, COX-2, TNF-α, IL-1β and IL-6 by suppressing the production of proinflammatory mediators and cytokines. Furthermore, UaB attenuated NF-κB activation by inhibiting the nuclear translocation of the transcription factor p65. LC-MS analysis with UaB revealed the presence of flavonol aglycones — quercetin (4) and kaempferol (6) — and their glycosylated derivatives — quercitrin (3), rutin (5), and kaempferol 3-O-rutinoside (7). Molecular docking analysis suggests that the major flavonol aglycones exhibited high affinity towards COX-2 NSAID-binding site, TNF-α and TACE, while the glycosylated flavonoids showed high affinity towards iNOS and IKK. The top protein-ligand complexes were found to be dynamically stable as shown by molecular dynamics simulations. This is the first report highlighting the mechanistic in silico and in vitro anti-inflammatory potential of U. alba.

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Computational and Experimental Assessments of Magnolol as a Neuroprotective Agent and Utilization of UiO-66(Zr) as Its Drug Delivery System

Cited by 20 publications

References 73 publications

Antituberculosis and Antiproliferative Activities of the Extracts and Tetrahydrobisbenzylisoquinoline Alkaloids from Phaeanthus ophthalmicus: In Vitro and In Silico Investigations

Antituberculosis and Antiproliferative Activities of the Extracts and Tetrahydrobisbenzylisoquinoline Alkaloids from Phaeanthus ophthalmicus: In Vitro and In Silico Investigations

In Silico Potentials of Alpinia galanga Constituents against Human Placental Aromatase Vital in Postmenopausal Estrogen-dependent Breast Cancer Pathogenesis

Flavonoids from Uvaria alba attenuate LPS-induced inflammatory responses by suppressing NF-κB activation in RAW 264.7 macrophages: In silico and in vitro perspectives

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