Histone deacetylases (HDACs) are part of a vast family of enzymes with crucial roles in numerous biological
processes, largely through their repressive influence on transcription, with serious implications in a variety of human
diseases. Among different isoforms, human HDAC2 in particular draws attention as a promising target for the treatment
of cancer and memory deficits associated with neurodegenerative diseases. Now the challenge is to obtain a compound
that is structurally novel and truly selective to HDAC2 because most current HDAC2 inhibitors do not show isoforms
selectivity and suffer from metabolic instability. In order to identify novel, and isoform-selective inhibitors for human
HDAC2, we designed a shape-based hybrid query from multiple scaffolds of known chemical classes and validated it to
be a more effective approach to discover diverse scaffolds than single-molecule query. The hybrid query-based screening
rendered a hit compound with the N-benzylaniline scaffold which showed moderate inhibitory activity against HDAC2,
and its chemical structure is diverse compared to known HDAC2 inhibitors. Notably, this compound shows the selectivity
against the HDAC6, a Class II enzyme, thus has the potential to further develop into the class- and isoform-selective
inhibitors. Our present study supplies an useful approach to identifying novel HDAC2 inhibitors, and can be extended to
the inquires of other important biomedical targets as well.
Keywords: HDAC2 inhibitor, N-benzylaniline, hybrid query, scaffold merging, shape-based screening.
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