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.
Cervical cancer ranks third among the most prevalent deadly cancer in women worldwide and ranks first in developing countries. It is caused by human papilloma virus (HPV) infection. Thus HDACs have become prominent inhibition target for cervical cancer treatment. In order to discover the new alternative HDAC inhibitors (HDACIs), we conducted a computer-aided drug discovery and development (CADDD) based on de novo approach. The compound library is based on 4-[(2-oxo-1,3-thiazolidin-3-yl)carbonyl] aniline. Screening of the best drug leads was evaluated from several parameters, such as docking and interaction analysis, pharmacology, in silico preclinical trial and molecular dynamics analysis. The inhibitory activity of these new designed ligands against Homo sapiens class II HDAC was determined by molecular docking simulation. Docking analysis yielded eight best ligands which have better binding affinity than the standards. Therefore, interaction analysis indicated that all best ligands performed coordination with Zn 2+ cofactor in HDAC charge-relay system which are essential for HDAC inhibitory activities of these inhibitors. Pharmacology analysis and preclinical trials of these compounds including pharmacology properties, bioactivity, mutagenicity-carcinogenicity, absorption, distribution, metabolism, excretion and toxicity (ADMET) properties were done through in silico methods. Through this analysis, the best ligands meet Lipinski's rule of five, have a better drug score than standards, and show good bioactivities, oral bioavailability and ADMET properties. All best ligands also have good synthetic accessibility and were proved to be new compounds that have never been synthesized
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