TY - JOUR
T1 - Synthesis, Enzyme Assays and Molecular Docking Studies of some known HDAC2 Inhibitors and Fluorinated Bioisosterics of Santacruzamate A
AU - Syed Musthakahmed, Muneer Ahmed
AU - Vermeulen, Koen
AU - Schnekenburger, Michael
AU - Moltzau, Lise
AU - Levy, Finn
AU - Marton, Janos
AU - Froeyen, Mathy
AU - Olberg, Dag
AU - Diederich, Marc
AU - Bormans, Guy
PY - 2017
Y1 - 2017
N2 - Background: Histone deacetylases (HDACs) emerged as important epigenetic regulators of gene expression. Method: In order to identify potential positron emission tomography (PET) tracers for imaging HDACs, we evaluated in vitro and in cellulo activities of some compounds that were reported as potent HDAC2-selective inhibitors. We observed marked differences between reported activity values and the values obtained in our assays for some of the compounds. To understand the structural basis of the activity of some of these inhibitors, we also performed molecular docking studies to understand their interaction patterns and binding modes with HDAC2. Results and Conclusion: We observed the low affinity compounds 4, 6 and 7 did not showed equal number of key ?-? interactions and hydrogen bonding when compared to high affinity compounds, and could be the possible reason for poor inhibition as reflected in in vitro assays. These preliminary experimental and computational results will help to interpret the HDAC affinity values of these key compounds with caution.
AB - Background: Histone deacetylases (HDACs) emerged as important epigenetic regulators of gene expression. Method: In order to identify potential positron emission tomography (PET) tracers for imaging HDACs, we evaluated in vitro and in cellulo activities of some compounds that were reported as potent HDAC2-selective inhibitors. We observed marked differences between reported activity values and the values obtained in our assays for some of the compounds. To understand the structural basis of the activity of some of these inhibitors, we also performed molecular docking studies to understand their interaction patterns and binding modes with HDAC2. Results and Conclusion: We observed the low affinity compounds 4, 6 and 7 did not showed equal number of key ?-? interactions and hydrogen bonding when compared to high affinity compounds, and could be the possible reason for poor inhibition as reflected in in vitro assays. These preliminary experimental and computational results will help to interpret the HDAC affinity values of these key compounds with caution.
KW - Enzyme assays
KW - HDAC
KW - HDAC inhibitors
KW - In vitro
KW - Molecular docking
KW - PET tracers
UR - http://www.scopus.com/inward/record.url?scp=85026672872&partnerID=8YFLogxK
U2 - 10.2174/1570180813666161101152943
DO - 10.2174/1570180813666161101152943
M3 - Article
VL - 14
SP - 787
EP - 797
JO - Letters in Drug Design and Discovery
JF - Letters in Drug Design and Discovery
SN - 1570-1808
IS - 7
ER -