Utilization of Boron Compounds for the Modification of Suberoyl Anilide Hydroxamic Acid as Inhibitor of Histone Deacetylase Class II Homo sapiens

Abstract

Histone deacetylase (HDAC) has a critical function in regulating gene expression. The inhibition of HDAC has developed as an interesting anticancer research area that targets biological processes such as cell cycle, apoptosis, and cell differentiation. In this study, an HDAC inhibitor that is available commercially, suberoyl anilide hydroxamic acid (SAHA), has been modified to improve its efficacy and reduce the side effects of the compound. Hydrophobic cap and zinc-binding group of these compounds were substituted with boron-based compounds, whereas the linker region was substituted with p-aminobenzoic acid. The molecular docking analysis resulted in 8 ligands with ΔG binding value more negative than the standards, SAHA and trichostatin A (TSA). That ligands were analyzed based on the nature of QSAR, pharmacological properties, and ADME-Tox. It is conducted to obtain a potent inhibitor of HDAC class II Homo sapiens. The screening process result gave one best ligand, Nova2 (513246-99-6), which was then further studied by molecular dynamics simulations.

Current data regarding the structure-toxicity relationship of boron-containing compounds

“…Recent studies have been trying to find strategies to identify highly toxic BCCs by employing analytical chemistry, the quantitative structure-activity relationship (Endo, 2003;Dembitsky, 2004;Zhang, 2014;Hansen, 2015;Pellizzaro, 2015), and/or computational predictive assays (Ciani, 2012;Kehlert, 2013;Bakri, 2014). Most of these studies have suggested that specific moieties in aryl or alkyl boronic acids are likely to be responsible for inducing cytotoxicity or mutagenicity (Pellizzaro, 2015).…”

“…These models are only able to predict whether compounds are toxic or non-toxic within a single toxicity class. Also, in silico analysis of BCCs has yielded limited results when using Lipinski's rule or predictors based on pharmacokinetics and pharmacodynamics (Bakri, 2014). With innovative strategies, some researchers are trying to build a multiclass model to predict several categories of toxicity (e.g., acute toxicity, mutagenicity, tumorigenicity, skin and eye irritation, reproductive effects and multiple dose effects) by using databases instead of only one or two toxicity endpoints (Chen, 2013;Raies, 2016).…”

Histone Deacetylase 2 (HDAC2) Inhibitors Containing Boron

“…Unsurprisingly, HDACi research over the past decade has focused on the design of HDAC3 and HDAC8 inhibitors due to their significant structural differences. [31,[52][53][54][55] To date, integration of boron moieties into HDAC inhibitors such as 1 has only had limited success, with their in vitro potency being surpassed by more traditional organic fragments. Previous work in this field has focussed on the re-design the skeletal structure of 1 by altering either 1) its linker or 2) Zn 2 + -binding domain to improve the drug's metal-complexation capability.…”

“…Indeed, such studies have solely focused on the use of boronic acids to coordinate to the Zn 2 + ion in Class I, II and IV HDACs but with only limited success. [29][30][31] To date, hydroxamic acid-based drugs such as 1 are still amongst the most potent inhibitors of Class I HDACs. [20,26,32,33] To the best of our knowledge, modification of the phenyl capping group in 1 with boron moieties has not been reported previously.…”

Pemanfaatan bioinformatika dalam bidang pertanian dan kesehatan (The utilization of bioinformatics in the field of agriculture and health)

“…Penggunaan piranti-piranti lunak daring tersebut banyak diarahkan untuk pengembangan obat dengue, avian influenza, dan kanker serviks (Wei et al, 2006;Lim et al, 2013;Bakri et al, 2014). Secara lebih detail, beberapa aspek penting dalam desain obat in silico meliputi: (1) metode komputasional pada polifarmakologi, (2) prediksi parameter farmakokinetik, (3) teknologi CADD pada desain obat secara in silico, (4) prediksi potensial aksi, (5) aplikasi OMICs di biologi sel punca, (6) komputasi basis data lncRNAs berbasis internet dibahas di dalam kajian ilmiah ini.…”