Title:Docking and QSAR Studies of Aryl-valproic Acid Derivatives to Identify Antiproliferative Agents Targeting the HDAC8
Volume: 17
Issue: 7
Author(s): Heidy Martínez-Pacheco, Guillermo Ramírez-Galicia, Midalia Vergara-Arias, Jurg Gertsch, Jonathan Manuel Fragoso-Vazquez, David Mendez-Luna, A. L. Abujamra, Cabrera-Perez Laura Cristina, Rosales-Hernandez Martha Cecilia, I Mendoza-Lujambio and Jose Correa-Basurto*
Affiliation:
- Laboratorio de Modelado Molecular y Diseño de Fármacos (Laboratory of Molecular Modelling and Drug Design), Escuela Superior de Medicina del Instituto Politécnico Nacional, Plan de San Luis y Salvador Díaz Mirón s/n, Casco de Santo Tomás, Mexico City, 11340,Mexico
Keywords:
Docking studies, QSAR studies, Artificial Neuron Network, Anticancer test, 2D-BCUT descriptors, derivatives.
Abstract: 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.
