Fevicordin-A (FevA) isolated from Phaleria macrocarpa (Scheff) Boerl. seeds was evaluated for its potential anticancer activity by in vitro and in silico approaches. Cytotoxicity studies indicated that FevA was selective against cell lines of human breast adenocarcinoma (MCF-7) with an IC50 value of 6.4 μM. At 11.2 μM, FevA resulted in 76.8% cell death of T-47D human breast cancer cell lines. Critical pharmacophore features amongst human Estrogen Receptor-α (hERα) antagonists were conserved in FevA with regard to a hypothesis that they could make notable contributions to its pharmacological activity. The binding stability as well as the dynamic behavior of FevA towards the hERα receptor in agonist and antagonist binding sites were probed using molecular dynamics (MD) simulation approach. Analysis of MD simulation suggested that the tail of FevA was accountable for the repulsion of the C-terminal of Helix-11 (H11) in both agonist and antagonist receptor forms. The flexibility of loop-534 indicated the ability to disrupt the hydrogen bond zipper network between H3 and H11 in hERα. In addition, MM/GBSA calculation from the molecular dynamic simulations also revealed a stronger binding affinity of FevA in antagonistic action as compared to that of agonistic action. Collectively, both the experimental and computational results indicated that FevA has potential as a candidate for an anticancer agent, which is worth promoting for further preclinical evaluation.
Previous studies have reported that compounds bearing
an arylamide
linked to a heterocyclic planar ring have successfully inhibited the
hemopexin-like domain (PEX9) of matrix metalloproteinase 9 (MMP9).
PEX9 has been suggested to be more selectively targeted than MMP9’s
catalytic domain in a degrading extracellular matrix under some pathologic
conditions, especially in cancer. In this study, we aim to synthesize
and evaluate 10 arylamide compounds as MMP9 inhibitors through an
enzymatic assay as well as a cellular assay. The mechanism of inhibition
for the most active compounds was investigated via molecular dynamics
simulation (MD). Molecular docking was performed using AutoDock4.0
with PEX9 as the protein model to predict the binding of the designed
compounds. The synthesis was carried out by reacting aniline derivatives
with 3-bromopropanoyl chloride using pyridine as the catalyst at room
temperature. The MMP9 assay was conducted using the FRET-based MMP9
kits protocol and gelatin zymography assay. The cytotoxicity assay
was done using the MTT method, and the MD simulation was performed
using AMBER16. Assay on MMP9 demonstrated activities of three compounds
(2, 7, and 9) with more than
50% inhibition. Further inhibition on MMP9 expressed by 4T1 showed
that two compounds (7 and 9) inhibited its
gelatinolytic activity more than 50%. The cytotoxicity assay against
4T1 cells results in the inhibition of the cell growth with an EC50 of 125 μM and 132 μM for 7 and 9, respectively. The MD simulation explained a stable interaction
of 7 and 9 in PEX9 at 100 ns with a free
energy of binding of −8.03 kcal/mol and −6.41 kcal/mol,
respectively. Arylamides have potential effects as selective MMP9
inhibitors in inhibiting breast cancer cell progression.
Human Epidermal Growth Factor Receptor-1 (EGFR), a transmembrane tyrosine kinase receptor (RTK), has been associated with several types of cancer, including breast, lung, ovarian, and anal cancers. Thus, the receptor was targeted by a variety of therapeutic approaches for cancer treatments. A series of chalcone derivatives are among the most highly potent and selective inhibitors of EGFR described to date. A series of chalcone derivatives were proposed in this study to investigate the intermolecular interactions in the active site utilizing molecular docking and molecular dynamics simulations. After a careful analysis of docking results, compounds 1a and 1d were chosen for molecular dynamics simulation study. Extensive hydrogen bond analysis throughout 7 ns molecular dynamics simulation revealed the ability of compounds 1a and 1d to retain the essential interactions needed for the inhibition, especially MET 93. Finally, MM-GBSA calculations highlight on the capability of the ligands to bind strongly within the active site with binding energies of −44.04 and −56.6 kcal/mol for compounds 1a and 1d, respectively. Compound 1d showed to have a close binding energy with TAK-285 (−66.17 kcal/mol), which indicates a high chance for compound 1d to exhibit inhibitory activity, thus recommending to synthesis it to test its biological activity. It is anticipated that the findings reported here may provide very useful information for designing effective drugs for the treatment of EGFR-related cancer disease.
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