Inhibition mechanism of SAHA in HDAC: a revisit

Abstract

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.

HDAC10 upregulation contributes to interleukin 1β‐mediated inflammatory activation of synovium‐derived mesenchymal stem cells in temporomandibular joint

“…is the most well-known and well-studied HDAC pan-inhibitor, its inhibition mechanism upon binding to HDAC is still controversial (Zhou, Wu, & Luo, 2015). In chondrocytes obtained from OA patients, SAHA inhibits the release of nitric oxide, MMP-1, and MMP-13 induced by IL-1β (Makki & Haqqi, 2016 (Mai et al, 2005).…”

Novel spiroindoline HDAC inhibitors: Synthesis, molecular modelling and biological studies

“…All compounds reported in this paper were treated by LigPrep application (LigPrep version 3.3, Schrödinger, LLC, New York, NY, 2015) in order to generate the most probable ionization state at cellular pH (7.4 ± 0.2) as reported by us [66,67]. Moreover, according to the evidences reported in literature [68][69][70][71][72][73], we used a neutral hydroxamic acid moiety of the spiroindoline compounds, since the hydroxamic acid proton should not be transferred in HDAC isoforms containing histidines in the binding site close to the reactive metal center, as in the case of HDAC1 and HDAC6.…”

Harnessing the Role of HDAC6 in Idiopathic Pulmonary Fibrosis: Design, Synthesis, Structural Analysis, and Biological Evaluation of Potent Inhibitors

“…Ligands were built in Maestro and minimized by MacroModel (MacroModel, Schrödinger Release 2016) software using OPLS-2005 as the force field. Moreover, the resulting compounds were treated by LigPrep application (LigPrep, Schrödinger Release 2016) to generate the most probable ionization state at the cellular pH (7.4 ± 0.2) as reported by us. , Moreover, according to the evidence reported in the literature, − we used a neutral hydroxamic acid moiety of the compounds since the hydroxamic acid proton should not be transferred in HDAC isoforms containing histidine residues in the binding site, close to the reactive metal center as in the case of HDAC1 and HDAC6. , …”