TY - JOUR
T1 - Prediction of the three-dimensional structures of histone deacetylase 1 complexed with romidepsin and FK-A5
AU - Oda, A.
AU - Kato, K.
AU - Morino, M.
AU - Nakayoshi, T.
AU - Fukuyoshi, S.
AU - Saijo, K.
AU - Ishioka, C.
AU - Kurimoto, E.
N1 - Funding Information:
This work was supported by Grants-in-Aid for Scientific Research (15H01064 and 17K08257) from the Japan Society for the Promotion of Science.
Funding Information:
Previously, we constructed an assay system to evaluate the inhibitory activities of PI3K inhibitors [4]. Using our assay system, we screened the chemical library of the Screening Committee of Anticancer Drugs supported by a Grant-in-Aid for Scientific Research on Innovative Areas and Scientific Support Programs for Cancer Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan [4, 5]. Via our screening, the HDAC inhibitor romidepsin and its analogs were identified as candidate compounds with PI3K inhibitory activities. Romidepsin is a natural bicyclic depsipeptide produced by Chromobacterium violaceum, and is known as a class I HDAC inhibitor. It was approved by the FDA for the treatment of cutaneous T-cell lymphoma and peripheral T-cell lymphoma. When a PI3K inhibitor was used in combination with an HDAC inhibitor, the cytocidal effect was enhanced [10]. Therefore, HDAC/PI3K dual inhibitors are promising compounds for the treatment of intractable cancer. Figure 1 depicts HDAC/PI3K dual inhibitor candidates found by our team. FK-A5 is the romidepsin analog that has the highest inhibitory activity for PI3K.
Publisher Copyright:
© 2018 by IOP Publishing Ltd.
PY - 2018/12/24
Y1 - 2018/12/24
N2 - Romidepsin is an anticancer drug that inhibits histone deacetylase (HDAC) in human cells. Recently, we found that romidepsin and its analog, FK-A5, inhibit phosphoinositide 3-kinase. Thus, romidepsin and FK-A5 are expected to be promising HDAC/PI3K dual inhibitors for anticancer therapy. In this study, the HDAC1-inhibitor complex structures were predicted by using computational docking and molecular dynamics (MD) simulations. Because romidepsin and FK-A5 are large cyclic molecules, large numbers of conformers can be obtained for these molecules by computational chemical treatment. The docking poses were extracted by comparing romidepsin and FK-A5 because similar compounds are recognized by proteins in similar binding modes. MD simulations were conducted for the selected docking poses, and the protein-ligand interactions were analyzed. The computational results are expected to be useful for the rational drug design of HDAC inhibitors.
AB - Romidepsin is an anticancer drug that inhibits histone deacetylase (HDAC) in human cells. Recently, we found that romidepsin and its analog, FK-A5, inhibit phosphoinositide 3-kinase. Thus, romidepsin and FK-A5 are expected to be promising HDAC/PI3K dual inhibitors for anticancer therapy. In this study, the HDAC1-inhibitor complex structures were predicted by using computational docking and molecular dynamics (MD) simulations. Because romidepsin and FK-A5 are large cyclic molecules, large numbers of conformers can be obtained for these molecules by computational chemical treatment. The docking poses were extracted by comparing romidepsin and FK-A5 because similar compounds are recognized by proteins in similar binding modes. MD simulations were conducted for the selected docking poses, and the protein-ligand interactions were analyzed. The computational results are expected to be useful for the rational drug design of HDAC inhibitors.
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U2 - 10.1088/1742-6596/1136/1/012019
DO - 10.1088/1742-6596/1136/1/012019
M3 - Conference article
AN - SCOPUS:85059417936
SN - 1742-6588
VL - 1136
JO - Journal of Physics: Conference Series
JF - Journal of Physics: Conference Series
IS - 1
M1 - 012019
T2 - 29th IUPAP Conference on Computational Physics, CCP 2017
Y2 - 9 July 2017 through 13 July 2017
ER -