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1.
Mol Divers ; 25(2): 1077-1089, 2021 May.
Article in English | MEDLINE | ID: mdl-32328963

ABSTRACT

Glutaminase plays an important role in carcinogenesis and cancer cell growth. This biological target is interesting against cancer cells. Therefore, in this work, in silico [docking and molecular dynamics (MD) simulations] and in vitro methods (antiproliferative and LC-MS metabolomics) were employed to assay a hybrid compound derived from glutamine and valproic acid (Gln-VPA), which was compared with 6-diazo-5-oxo-L-norleucine (DON, a glutaminase inhibitor) and VPA (contained in Gln-VPA structure). Docking results from some snapshots retrieved from MD simulations show that glutaminase recognized Gln-VPA and DON. Additionally, Gln-VPA showed antiproliferative effects in HeLa cells and inhibited glutaminase activity. Finally, the LC-MS-based metabolomics studies on HeLa cells treated with either Gln-VPA (IC60 = 8 mM) or DON (IC50 = 3.5 mM) show different metabolomics behaviors, suggesting that they modulate different biological targets of the cell death mechanism. In conclusion, Gln-VPA is capable of interfering with more than one pharmacological target of cancer, making it an interesting drug that can be used to avoid multitherapy of classic anticancer drugs.


Subject(s)
Antineoplastic Agents , Glutamine , Valproic Acid , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Cell Survival/drug effects , Chromatography, Liquid , Glutaminase/antagonists & inhibitors , Glutaminase/chemistry , Glutamine/chemistry , Glutamine/pharmacology , HeLa Cells , Humans , Mass Spectrometry , Metabolome/drug effects , Metabolomics , Models, Molecular , Valproic Acid/chemistry , Valproic Acid/pharmacology
2.
Anticancer Agents Med Chem ; 16(11): 1485-1490, 2016.
Article in English | MEDLINE | ID: mdl-26845132

ABSTRACT

In this contribution, we focused on evaluating a novel compound developed by our group. This molecule, derived from glutamine (Gln) and valproic acid (VPA), denominated (S)- 5-amino-2-(heptan-4-ylamino)-5-oxopentanoic acid (Gln-VPA), was submitted to docking studies on histone deacetylase 8 (HDAC8) to explore its non-bonded interactions. The theoretical results were validated in HeLa cells as a cancer cell model and in human dermal fibroblasts as a normal cell model. The effects of Gln-VPA on HeLa and normal fibroblasts in terms of cell survival and the ability to inhibit HDAC activity in nude nuclear proteins and in nuclear proteins of whole cells treated for 24 h were analyzed. The HeLa cell cycle was analyzed after 24 and 48 h of treatment with Gln-VPA. The docking studies show that Gln-VPA can reach the catalytic site of HDAC8. Gln-VPA was organically synthesized with a purity greater than 97%, and its structure was validated using mass spectrometry, nuclear magnetic resonance and infrared spectroscopy. Gln-VPA showed a similar effect to VPA as an HDAC inhibitor but with less toxicity to fibroblasts. Although Gln-VPA was less efficient than VPA in reducing the survival of HeLa cells, it could be studied for use as a cancer cell sensitizer.


Subject(s)
Antineoplastic Agents/pharmacology , Glutamine/analogs & derivatives , Histone Deacetylase Inhibitors/pharmacology , Molecular Docking Simulation , Repressor Proteins/antagonists & inhibitors , Valproic Acid/analogs & derivatives , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Fibroblasts/drug effects , Glutamine/chemical synthesis , Glutamine/chemistry , Glutamine/pharmacology , HeLa Cells , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylases/metabolism , Humans , Molecular Structure , Repressor Proteins/metabolism , Structure-Activity Relationship , Valproic Acid/chemical synthesis , Valproic Acid/chemistry , Valproic Acid/pharmacology
3.
J Biomol Struct Dyn ; 33(10): 2161-72, 2015.
Article in English | MEDLINE | ID: mdl-25587872

ABSTRACT

The G-protein coupled estrogen receptor 1 GPER/GPR30 is a transmembrane seven-helix (7TM) receptor involved in the growth and proliferation of breast cancer. Due to the absence of a crystal structure of GPER/GPR30, in this work, molecular modeling studies have been carried out to build a three-dimensional structure, which was subsequently refined by molecular dynamics (MD) simulations (up to 120 ns). Furthermore, we explored GPER/GPR30's molecular recognition properties by using reported agonist ligands (G1, estradiol (E2), tamoxifen, and fulvestrant) and the antagonist ligands (G15 and G36) in subsequent docking studies. Our results identified the E2 binding site on GPER/GPR30, as well as other receptor cavities for accepting large volume ligands, through GPER/GPR30 π-π, hydrophobic, and hydrogen bond interactions. Snapshots of the MD trajectory at 14 and 70 ns showed almost identical binding motifs for G1 and G15. It was also observed that C107 interacts with the acetyl oxygen of G1 (at 14 ns) and that at 70 ns the residue E275 interacts with the acetyl group and with the oxygen from the other agonist whereas the isopropyl group of G36 is oriented toward Met141, suggesting that both C107 and E275 could be involved in the protein activation. This contribution suggest that GPER1 has great structural changes which explain its great capacity to accept diverse ligands, and also, the same ligand could be recognized in different binding pose according to GPER structural conformations.


Subject(s)
Benzodioxoles/chemistry , Estradiol/analogs & derivatives , Estradiol/chemistry , Quinolines/chemistry , Receptors, Estrogen/chemistry , Receptors, G-Protein-Coupled/chemistry , Tamoxifen/chemistry , Amino Acid Motifs , Binding Sites , Fulvestrant , Humans , Hydrogen Bonding , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Sequence Data , Protein Binding , Protein Structure, Secondary , Protein Structure, Tertiary , Receptors, Estrogen/antagonists & inhibitors , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/antagonists & inhibitors , Thermodynamics
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