Design, virtual screening, molecular docking and molecular dynamics studies of novel urushiol derivatives as potential HDAC2 selective inhibitors

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 binding affinity toward HDAC2 of the compounds was screened by Glide docking. The best scoring compounds were processed further with molecular docking, MD simulations and binding free energy studies to analyze the binding modes and mechanisms. Six compounds, 21, 23, 10, 19, 9 and 30, gave Glide scores of -7.9 to -8.5, which revealed that introducing -F, -CI, triazole, benzamido, formamido, hydroxyl or nitro substituents onto the benzene ring could increase binding affinity significantly. Molecular docking studies revealed that zinc ion coordination, hydrogen bonding and hydrophobic interactions contributed to the high calculated binding affinities of these compounds toward HDAC2 and that His145, His146, Gly154, Glu103, His183, Asp104, Tyr308 and Phe155 contributed favorably to the binding. 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. van der Waals and electrostatic interactions provided major contributions to the stability of these complexes. These results show the promising potential of urushiol derivatives as potent HDAC2 binding lead compounds.