A Structure‐Based Virtual Screening Approach toward the Discovery of Histone Deacetylase Inhibitors: Identification of Promising Zinc‐Chelating Groups

Abstract

The inhibitors of histone deacetylases (HDACs) have drawn a great deal of attention due to their promising potential as small-molecule therapeutics for the treatment of cancer. By means of virtual screening with docking simulations under consideration of the effects of ligand solvation, we were able to identify six novel HDAC inhibitors with IC(50) values ranging from 1 to 100 muM. These newly identified inhibitors are structurally diverse and have various chelating groups for the active site zinc ion, including N-[1,3,4]thiadiazol-2-yl sulfonamide, N-thiazol-2-yl sulfonamide, and hydroxamic acid moieties. The former two groups are included in many drugs in current clinical use and have not yet been reported as HDAC inhibitors. Therefore, they can be considered as new inhibitor scaffolds for the development of anticancer drugs by structure-activity relationship studies to improve the inhibitory activities against HDACs. Interactions with the HDAC1 active site residues responsible for stabilizing these new inhibitors are addressed in detail.

Insight into the Recognition, Binding, and Reactivity of Catalytic Metallodrugs Targeting Stem Loop IIb of Hepatitis C IRES RNA

“…A value of +0.8 is used to simulate the +2 charge in order to compensate for the tendency of Autodock to overestimate electrostatic interactions. [33] The geometry around the metal was based on the X-ray crystal structure of Cu-GGH and was restricted to a square planar configuration. [17] a Lamarckian Genetic Algorithm and the following parameters were used for docking: population size of 150, a random starting position and conformation, a maximal mutation of 2Å in translation and 50° in rotations (elitism of 5), iterations of Solis and Wets local search of 300, torsional degrees of freedom of 23 for the peptide complex, an external grid energy of 1000 kcal/mol, a mutation rate of 0.02 and a crossover rate of 0.8, and local search rate of 0.06.…”

Computer- and structure-based lead design for epigenetic targets

“…The authors were able to identify six novel HDAC inhibitors with IC 50 values in the low micromolar range using the commercially available BIOMOL HDAC fluorescence assay. 65 Interestingly, these inhibitors contain zinc-chelating groups not previously reported for HDAC inhibitors, including the N- [1,3,4]thiadiazol-2-yl-sulfonamide group (compounds 8-10, Fig. 5).…”

“…65 Park et al docked 180,000 molecules from the InterBioScreen database into homology model of HDAC1. The model had been validated by docking known inhibitors of HDAC1 into the model structure.…”

Exploration of the binding pocket of histone deacetylases: the design of potent and isoform-selective inhibitors

“…In addition, novel inhibitors can be predicted in silico by probing a database of a large chemical library. For instance, both structure-based and ligand-based virtual screenings have been applied for identification of selective HDAC inhibitors (Liu et al, 2010;Park et al, 2010;Wang et al, 2013) with the most recent study by Huang et al (2016), in which virtual screening and experimental validation of HDAC8 inhibitors was performed. Other modeling approaches including pharmacophore modeling (Chen et al, 2008), flexible docking, and three-dimensional QSAR (3D-QSAR) (Nair et al, 2012) have been used for the identification of selective HDAC inhibitors.…”