TY - JOUR
T1 - Molecular modeling and LC–MS-based metabolomics of a glutamine-valproic acid (Gln-VPA) derivative on HeLa cells
AU - Fragoso-Vázquez, M. J.
AU - Méndez-Luna, D.
AU - Rosales-Hernández, M. C.
AU - Luna-Palencia, G. R.
AU - Estrada-Pérez, A.
AU - Fromager, Benedicte
AU - Vásquez-Moctezuma, I.
AU - Correa-Basurto, J.
N1 - Publisher Copyright:
© 2020, Springer Nature Switzerland AG.
PY - 2021/5
Y1 - 2021/5
N2 - 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. Graphic abstract: [Figure not available: see fulltext.].
AB - 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. Graphic abstract: [Figure not available: see fulltext.].
KW - Anti-proliferative LC–MS-based metabolomic
KW - Dual-target inhibitor
KW - Gln-VPA
KW - Glutaminase
UR - http://www.scopus.com/inward/record.url?scp=85084128673&partnerID=8YFLogxK
U2 - 10.1007/s11030-020-10089-z
DO - 10.1007/s11030-020-10089-z
M3 - Artículo
C2 - 32328963
AN - SCOPUS:85084128673
SN - 1381-1991
VL - 25
SP - 1077
EP - 1089
JO - Molecular Diversity
JF - Molecular Diversity
IS - 2
ER -
