It must be admitted that cancer is a widespread disease with a high mortality rate. Other than genetic factors, the development of cancer touches upon epigenetic modifications, including covalent modifications of DNA (methylation and demethylation) and histones [1]. The post-translational modification of histones will form the so-called "histone code", which provides a recognition marker that regulates gene transcription by inducing the synergistic or antagonistic effect on the binding of additional proteins to DNA [2, 3]. Histone deacetylases (HDACs) pertain to the category of Zn2+ or nicotinamide adenine dinucleotide (NAD+)-dependent proteolytic enzymes, which could dislodge acetyl groups from the ε-amino group of lysine residues located at the N-terminus of core histones [4, 5]. On account of the deacetylation property, HDACs partake in the regulation and modulation of a large amount of momentous biological signaling pathways, including cell differentiation, proliferation, angiogenesis and apoptosis [6]. Up to the present, a total of 18 HDAC isozymes have been identified in humans. HDACs are classified into 4 disparate classes on the grounds of their structural, number of catalytically active sites and the sequence homology to the yeast original enzymes [7]. Among the rest, classes I (1, 2, 3, 8), II (4, 5, 6, 7, 9, 10) and IV (11) HDACs belong to Zn2+-dependent metalloenzymes, while class Ⅲ (SIRT1-7) are NAD+-dependent HDACs [8].
Meanwhile, HDACs attract more and more attention from the academia and pharmaceutical industry [9]. There is plenty of evidence that HDACs overexpression has been discovered in all sorts of human cancers, including myeloma, gastric, pancreatic, colorectal and prostate cancers [10]. With the gradual elucidation of the relationship between HDACs and tumors, it has been widely recognized that HDACs have emerged as extremely attractive targets for the discovery of anticancer agents. Regrettably, only a smattering of promising HDAC enzyme inhibitors, which block the cancer-preventing process, have been tested and evaluated in various stages of clinical trials during the lengthy discovery process. Until now, only five HDAC inhibitors namely, Vorinostat (SAHA), Romidepsin (FK228), Belinostat (PXD101), Panobinostat (LBH589) and Pracinostat (SB939) were resoundingly authorized by the United States Food and Drug Administration and one HDAC inhibitor namely Chidamide (CS055) obtained the approval from the China Food and Drug Administration [11, 12]. Both of them are approved for the treatment of cutaneous T-cell lymphoma, peripheral T-cell lymphoma or multiple myeloma [13]. Although HDAC inhibitors reveal potent antitumor effects, most broad-spectrum HDAC inhibitors may cause severe side effects of which the most common symptoms were thrombocytopenia, neutropenia, anemia, fatigue, and diarrhea [14]. Therefore, the development of novel and efficient HDAC inhibitors with high selectivity and low toxicity has the potential to profoundly tap their clinical potential in cancer therapy [15].
Three-dimensional quantitative structure activity relationship (3D-QSAR) is one of the computational methods for drug design based on ligands and plays a crucial role in computer-aided drug design [16]. At the same time, quantitative relationships between a sequence of compounds and the associated biological activity have been explored using theoretical calculations and statistical analysis tools, providing some useful clues to the structural modifications of the compounds. On account of the high-precision features of the Comparative Molecular Field Method (CoMFA) and Comparative Molecular Similarity Analysis (CoMSIA) models, they have emerged as the most resultful 3D-QSAR tools based on statistical techniques [17]. In CoMFA, biological activity is related to steric and electrostatic parameters. Whereas the advantage of CoMSIA is its takes into account five different property fields: hydrophobic, hydrogen bond donor (HBD), hydrogen bond acceptor (HBA), steric field and electrostatic parameters [18]. The purpose of this research work is to produce a model with high predictive power, to provide more informed directions for further structural modifications, and to guide the design of novel high-potency HDAC inhibitors with specific inhibitory effects.