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ACS Chem Neurosci. 2019 Feb 26. doi: 10.1021/acschemneuro.8b00729. [Epub ahead of print]

How Does Chirality Determine the Selective Inhibition of Histone Deacetylase 6? A Lesson from Trichostatin A Enantiomers Based on Molecular Dynamics.

Author information

1
Lab of Innovative Drug Research and Bioinformatics, College of Pharmaceutical Sciences , Zhejiang University , Hangzhou 310058 , China.
2
Innovative Drug Research and Bioinformatics Group, School of Pharmaceutical Sciences and Collaborative Innovation Center for Brain Science , Chongqing University , Chongqing 401331 , China.
3
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry , Lanzhou University , Lanzhou 730000 , China.
4
Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital , Zhejiang University , Hangzhou 310000 , China.

Abstract

Histone deacetylase 6 (HDAC6) plays a key role in a variety of neurological disorders, which makes it attractive drug target for the treatment of Alzheimer's disease, Parkinson's disease, and memory/learning impairment. The selectivity of HDAC6 inhibitors (sHDAC6Is) are widely considered to be susceptible to the sizes of their Cap group and the physicochemical properties of their linker or zinc-binding group, which makes the discovery of new sHDAC6Is extremely difficult. With the discovery of the distinct selectivity between Trichostatin A (TSA) enantiomers, the chirality residing in the connective units between TSA's Cap and linker shows a great impact on its selectivity. However, the mechanism underlining ( S)-TSA's selectivity is still elusive, and the way chirality switches the selective ( S)-TSA to nonselective ( R)-TSA is unknown. In this study, multiple computational approaches were collectively applied to explore, validate, and differentiate the binding modes of two TSA enantiomers in HDACs (especially the HDAC6) at atomic level. First, two nonconservative residues (G200/M205 and Y197/F202 in HDAC1/6) in loop3 and four conservative residues deep inside the hydrophobic binding pocket were discovered as the decisive residues of ( S)-TSA's selectivity toward HDAC6. Then, a novel mechanism underlying the selectivity of ( S)-TSA toward HDAC6 was proposed, which was composed of the trigger by two nonconservative residues F202 and M205 in HDAC6 and a subsequently improved fit of ( S)-TSA deep inside HDAC6's hydrophobic binding pocket. TSA enantiomers were used as a molecular probe to explore the mechanism underlying sHDAC6Is' selectivity in this study. Because of their decisive roles in ( S)-TSA's selectivity to HDAC6, both F202 and M205 in HDAC6 should be especially considered in the discovery of novel sHDAC6Is.

KEYWORDS:

Selective HDAC6 inhibitor; Trichostatin A; chirality; molecular dynamics; neurodegenerative disease

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