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Anticancer Agents Med Chem. 2017;17(7):927-940. doi: 10.2174/1871520616666161019143219.

Docking and QSAR Studies of Aryl-valproic Acid Derivatives to Identify Antiproliferative Agents Targeting the HDAC8.

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Universidad del Papaloapan, Circuito Central 200, Parque Industrial, 68301 Tuxtepec, Oaxaca. Mexico.
Instituto de Química Aplicada, Universidad del Papaloapan, Circuito Central 200, Parque Industrial, 68301 Tuxtepec, Oaxaca. Mexico.
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.
Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, CH-3012 Bern. Switzerland.
Departamento de Química Orgánica, Escuela Nacional de Ciencias, Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala, Col. Casco de Santo Thomas. Mexico.
Graduate Program in Biotechnology, UNIVATES, Rio Grande do Sul. Brazil.



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.


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.


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.


2D-BCUT descriptors; Anticancer test; Artificial Neuron Network; Docking studies; QSAR studies; derivatives

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