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

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Structural Biology

Background:

• The second catalytic domain of human histone deacetylase 6 (HDAC6 CDII) possesses unique structural characteristics.
• HDAC6 CDII is primarily responsible for the enzymatic activity of the HDAC6 isoform.

Purpose of the Study:

• To identify novel fragments serving as selective zinc binding groups (ZBGs) for HDAC6 CDII.
• To develop new selective inhibitors targeting HDAC6 CDII.

Main Methods:

• Design of two fragment libraries: one with known chelators, another from the ZINC15 database.
• Structure-based virtual screening of designed libraries.
• Molecular docking and molecular dynamics simulations for fragment evaluation.

Main Results:

• Promising fragments were identified through virtual screening.
• An interesting benzimidazole fragment was selected.
• The benzimidazole fragment demonstrated potential as a ZBG for HDAC6 CDII.

Conclusions:

• The identified benzimidazole fragment is a potential ZBG for developing novel HDAC6 selective inhibitors.
• This research contributes to the field of targeted epigenetic drug discovery.