Computational Exploration of Zinc Binding Groups for HDAC Inhibition

Abstract

Histone deacetylases (HDACs) emerged as important drug targets in epigenetics. The most common HDAC inhibitors use hydroxamic acids as zinc binding groups despite unfavorable pharmacokinetic properties. A two-stage protocol of M05-2X calculations of a library of 48 fragments in a small model active site, followed by QM/MM hybrid calculations of the full enzyme with selected binders is used to prospectively select potential bidentate zinc binders. The energetics and interaction patterns of several zinc binders not previously used for the inhibition of HDACs are discussed.

Synthesis and biological evaluation of santacruzamate A analogues for anti-proliferative and immunomodulatory activity

“…The two terminal hydrogen bonds may form hydrogen bonding and hydrogen shuttling networks by sharing or fully transferring the hydrogen species between themselves and Asp186 and Asp179 adjacent to His146 and His145 respectively (see Figure S2 in Supplementary Material). 42 The delocalization of electron density via hydrogen bonding and hydrogen shuttling within this network may also further stabilize and enable the terminal oxygen species to donate electron density to the zinc ion.…”

“…This additional water molecule may prevent SCA from obtaining a favorable binding orientation to the zinc ion, although it may also be possible that without a bidentate chelator, the zinc ion may exist in a 5-coordination state. 42 The inability of SCA to form a favorable orientation to facilitate chelation may be further inhibited by the extended planar geometry of the terminal ethyl carbamate, potentially impeding the carbonyl oxygen from obtaining optimal orientation. Another issue with SCA binding involves the inability to stabilize the molecule in the binding pocket via hydrogen bonding with Asp104, His146, and His 145, since these residues are not situated properly when the carbamate terminus is coordinated with the zinc ion (Fig.…”

Histone deacetylases: structural determinants of inhibitor selectivity

“…However, upon coordination of the zinc ion, the pK a of hydroxamic acids would be reduced by approximately three units, the acidic proton being transferred to the adjacent conserved histidine (H669 in HDAC7) [80]. Interestingly, computational studies [41,66,[81][82][83] indicate that the anionic hydroxamate chelates the zinc ion in a bidentate fashion with geometries close to the experimental ones. However, whether the hydroxamic acids bind HDAC by adopting a neutral or anionic form is still matter of debate, and further investigations will be necessary to draw more definitive conclusions.…”

Calorimetric studies of the interactions of metalloenzyme active site mimetics with zinc-binding inhibitors

“…In addition, AHA has been studied for binding to zinc complexes using potentiometric methods, 16 and is a model for the structure of the hydroxamate class of ligands, which can bind a variety of metals. 23 In addition, the 8-HQ scaffold has been identified as a promising basis for the development of MMP inhibitors by Cohen and coworkers. 8-HQ binds Zn 2+ in a bidentate fashion through its phenolic oxygen and sp 2 nitrogen.…”