Inhibition mechanism of SAHA in HDAC: a revisit.
SAHA (vorinostat, Merck) is a famous clinical drug for zinc-containing histone deacetylase (HDAC) targets against cancer and several other human disorders, whose inhibition mechanism (namely the protonation mechanism) upon binding to HDAC has been debated for more than ten years. It is very challenging to verify experimentally and is still controversial theoretically. The popular "Class-dependent" (namely "Tyr-dependent") hypothesis is that the deprotonation of SAHA is mostly regulated by the conserved Tyr308 in class I HDAC while it is replaced by the His843 in class IIa HDAC. Herein, by elaborate QM(DFT)/MM MD simulations, we exclude the prevalent "Class-dependent" mechanism and advance a novel "Metal-dependent" mechanism, where the remote second metal site (K(+) in most HDAC and Ca(2+) in HDAC2) determines the protonation of SAHA. This proof-of-principle "Metal-dependent" mechanism opens up a new avenue to utilize the second metal site for isoform-selective inhibitor design.
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China. luohb77@mail.sysu.edu.cn wurb3@mail.sysu.edu.cn.
Jingwei
J
Zhou
Ruibo
R
Wu
Hai-Bin
HB
Luo
D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000187:drug effects*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D000077337:Vorinostat
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D006655:Histone Deacetylases