Novel urushiol derivatives as HDAC8 inhibitors: rational design, virtual screening, molecular docking and molecular dynamics studies

Abstract

Three series of novel urushiol derivatives were designed by introducing a hydroxamic acid moiety into the tail of an alkyl side chain and substituents with differing electronic properties or steric bulk onto the benzene ring and alkyl side chain. The compounds' binding affinity toward HDAC8 was screened by Glide docking. The highest-scoring compounds were processed further with molecular docking, MD simulations, and binding free energy studies to analyze the binding modes and mechanisms. Ten compounds had Glide scores of -8.2 to -10.2, which revealed that introducing hydroxy, carbonyl, amino, or methyl ether groups into the alkyl side chain or addition of -F, -Cl, sulfonamide, benzamido, amino, or hydroxy substituents on the benzene ring could significantly increase binding affinity. Molecular docking studies revealed that zinc ion coordination, hydrogen bonding, and hydrophobic interactions contributed to the high calculated binding affinities of these compounds toward HDAC8. MD simulations and binding free energy studies showed that all complexes possessed good stability, as characterized by low RMSDs, low RMSFs of residues, moderate hydrogen bonding and zinc ion coordination and low values of binding free energies. Hie147, Tyr121, Phe175, Hip110, Phe119, Tyr273, Lys21, Gly118, Gln230, Leu122, Gly269, and Gly107 contributed favorably to the binding; and Van der Waals and electrostatic interactions provided major contributions to the stability of these complexes. These results show the potential of urushiol derivatives as HDAC8 binding lead compounds, which have great therapeutic potential in the treatment of various malignancies, neurological disorders, and human parasitic diseases.

Novel C15 Triene Triazole, D-A Derivatives Anti-HepG2, and as HDAC2 Inhibitors: A Synergy Study

“…Our research results have suggested that the binding pattern of urushiol derivative ligands such as ligand compound 4 to the HDAC2 receptor [ 23 , 24 ] could be detected by the molecular docking technique. We attained the HDAC2 X-ray crystal structure (PDB no.…”

“…Notably, our research has indicated that the urushiol derivatives have a remarkable binding affinity with good scoring of histone deacetylase (HDAC)2 and HDAC8 [ 23 , 24 ]. Histone deacetylases (HDACs) are a group of zinc metalloenzymes that regulate chromatin remodeling and gene transcription by catalyzing the removal of an acetyl group moiety from the Ɛ-amino groups of the lysine residues on the amino terminal tails of the core histones [ 25 ].…”

“…On account of the continuation of the discovery of new antitumor compounds from natural products, it is of great interest to us to synthesize and synergize product-based antitumor agents. Considering urushiol’s anticancer activities and its structural similarities to Suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor, we sought to find some novel urushiol derivatives as potential HDAC2-selective inhibitors, in order to detect more valuable candidates for antitumor therapy [ 23 , 24 ]. Herein, we designed and synthesized a series of novel derivatives from readily available C15 triene urushiol, and tested their antitumor activities against human hepatocellular carcinoma (HepG2).…”

Histone Deacetylase Inhibitors and Antioxidants From the Root of Gluta usitata

“…The structure elucidation of (−)-eriodictyol (4), (−)-dihydroquercetin (5), and (−)-fustin (6) were determined by Infrared spectroscopy (IR), NMR, and electronic circular dichroism analysis as described in the previous report. 6…”

“…[2][3][4] Some urushiol derivatives have been evaluated as histone deacetylase 8 (HDAC8) inhibitors by molecular docking study. 5 Recently, we have reported the chemical constituents from the twigs and the flowers of this plant. 6,7 To the best of our knowledge, no compounds from the root of this plant have been reported.…”