TY - JOUR
T1 - Docking and QSAR studies of aryl-valproic acid derivatives to identify antiproliferative agents targeting the HDAC8
AU - Martínez-Pacheco, Heidy
AU - Ramírez-Galicia, Guillermo
AU - Vergara-Arias, Midalia
AU - Gertsch, Jürg
AU - Fragoso-Vázquez, Manuel Jonathan
AU - Méndez-Luna, David
AU - Abujamra, A. L.
AU - Cristina, Cabrera Pérez Laura
AU - Cecilia, Rosales Hernández Martha
AU - Mendoza-Lujambio, I.
AU - Correa-Basurto, JosÉ
N1 - Publisher Copyright:
© 2017, Bentham Science Publishers.
PY - 2017
Y1 - 2017
N2 - Background: Histone deacetylase 8 (HDAC8) is a plausible target for the development of novel anticancer drugs using a metal-chelating group and hydrophobic moieties as pharmacophores. It is known that valproic acid (administered as its salt, sodium valproate; VPANa+) is an HDAC8 inhibitor characterized by its hydrophobic chains. Nevertheless, VPA is hepatotoxic and VPA analogues might be explored for less hepatotoxic antiproliferative compounds. Method: In this work, docking and QSAR studies of 500 aryl-VPA derivatives as possible HDAC8 inhibitors were performed in order to explore and select potential anti-proliferative compounds. Docking results identified π−π, hydrogen bonds as the most important noncovalent interactions between HDAC8 (PDB: 3F07) and the ligands tested, whereas Belm4 was the best QSAR descriptor and classified as a 2D-BCUT descriptor. Result: Based on theoretical studies, compound DAVP042 was synthesized and evaluated in vitro for its antiproliferative activities on several cancer cell lines (A549-lung, MCF-7-breast, HCT116-colon and U937- lymphoid tissue) in comparison to VPA, as well as for its inhibitory activity on HDAC8 using in vitro models. DAVP042 demonstrated to have antiproliferative activity on all cancer cell lines employed, not only suggesting that this compound should be further studied, but also demonstrating that the methodology herein employed is appropriated to identify new therapeutic candidates.
AB - Background: Histone deacetylase 8 (HDAC8) is a plausible target for the development of novel anticancer drugs using a metal-chelating group and hydrophobic moieties as pharmacophores. It is known that valproic acid (administered as its salt, sodium valproate; VPANa+) is an HDAC8 inhibitor characterized by its hydrophobic chains. Nevertheless, VPA is hepatotoxic and VPA analogues might be explored for less hepatotoxic antiproliferative compounds. Method: In this work, docking and QSAR studies of 500 aryl-VPA derivatives as possible HDAC8 inhibitors were performed in order to explore and select potential anti-proliferative compounds. Docking results identified π−π, hydrogen bonds as the most important noncovalent interactions between HDAC8 (PDB: 3F07) and the ligands tested, whereas Belm4 was the best QSAR descriptor and classified as a 2D-BCUT descriptor. Result: Based on theoretical studies, compound DAVP042 was synthesized and evaluated in vitro for its antiproliferative activities on several cancer cell lines (A549-lung, MCF-7-breast, HCT116-colon and U937- lymphoid tissue) in comparison to VPA, as well as for its inhibitory activity on HDAC8 using in vitro models. DAVP042 demonstrated to have antiproliferative activity on all cancer cell lines employed, not only suggesting that this compound should be further studied, but also demonstrating that the methodology herein employed is appropriated to identify new therapeutic candidates.
KW - 2D-BCUT descriptors
KW - Anticancer test
KW - Artificial neuron network
KW - Derivatives
KW - Docking studies
KW - QSAR studies
UR - http://www.scopus.com/inward/record.url?scp=85025161822&partnerID=8YFLogxK
U2 - 10.2174/1871520616666161019143219
DO - 10.2174/1871520616666161019143219
M3 - Artículo de revisión
C2 - 27774878
SN - 1871-5206
VL - 17
SP - 927
EP - 940
JO - Anti-Cancer Agents in Medicinal Chemistry
JF - Anti-Cancer Agents in Medicinal Chemistry
IS - 7
ER -