Structure-based design of selective histone deacetylase 6 zinc binding groups

Abstract

The binding site of the second catalytic domain of human histone deacetylase 6 (HDAC6 CDII) has structural features that differ from the other human orthologues, being also mainly responsible for the overall enzymatic activity of this isoform. Aiming to identify new fragments as a possible novel selective zinc binding group (ZBG) for HDAC6 CDII, two fragment libraries were designed: one library consisting of known chelators and a second one using the fragments of the ZINC15 database. The most promising fragments identified in a structure-based virtual screening of designed libraries were further evaluated through molecular docking and molecular dynamics simulations. An interesting benzimidazole fragment was selected from the in silico studies and presented as potential zing binding group for the development of novel HDAC6 selective inhibitors.

Communicated by Ramaswamy H. Sarma

Graphical Abstract

Keywords:

• Histone deacetylase
• fragment-based drug design
• molecular docking
• epigenetics
• zinc binding group

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the COST-Action CM1406 “Epigenetic Chemical Biology (EpiChemBio)”. Molecular dynamics simulations were run on the PARADOX‐IV supercomputing facility at the Scientific Computing Laboratory, National Center of Excellence for the Study of Complex Systems, Institute of Physics, Belgrade, supported, in part, by the Ministry of Education, Science, and Technological Development of the Republic of Serbia under project no. ON171017. DR, NDj and KN kindly acknowledge Ministry of Science and Technological Development of the Republic of Serbia, Contract No. 172033.