| SIMOBEN, Conrad V., Dina ROBAA, Alokta CHAKRABARTI, Karin SCHMIDTKUNZ, Martin MAREK, Julien LANCELOT, Srinivasaraghavan KANNAN, Jelena MELESINA, Tajith B. SHAIK, Raymond J. PIERCE, Christophe ROMIER, Manfred JUNG a Wolfgang SIPPL. A Novel Class of Schistosoma mansoni Histone Deacetylase 8 (HDAC8) Inhibitors Identified by Structure-Based Virtual Screening and In Vitro Testing. Molecules. BASEL: Mayer und Muller, 2018, roč. 23, č. 3, s. 1-14. ISSN 1420-3049. Dostupné z: https://dx.doi.org/10.3390/molecules23030566. |
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@article{1495516,
author = {Simoben, Conrad V. and Robaa, Dina and Chakrabarti, Alokta and Schmidtkunz, Karin and Marek, Martin and Lancelot, Julien and Kannan, Srinivasaraghavan and Melesina, Jelena and Shaik, Tajith B. and Pierce, Raymond J. and Romier, Christophe and Jung, Manfred and Sippl, Wolfgang},
article_location = {BASEL},
article_number = {3},
doi = {http://dx.doi.org/10.3390/molecules23030566},
keywords = {epigenetics; crystal structure; docking; histone deacetylase (HDAC) inhibitors; schistosomiasis; virtual screening},
language = {eng},
issn = {1420-3049},
journal = {Molecules},
title = {A Novel Class of Schistosoma mansoni Histone Deacetylase 8 (HDAC8) Inhibitors Identified by Structure-Based Virtual Screening and In Vitro Testing},
url = {https://www.mdpi.com/1420-3049/23/3/566},
volume = {23},
year = {2018}
}
TY - JOUR
ID - 1495516
AU - Simoben, Conrad V. - Robaa, Dina - Chakrabarti, Alokta - Schmidtkunz, Karin - Marek, Martin - Lancelot, Julien - Kannan, Srinivasaraghavan - Melesina, Jelena - Shaik, Tajith B. - Pierce, Raymond J. - Romier, Christophe - Jung, Manfred - Sippl, Wolfgang
PY - 2018
TI - A Novel Class of Schistosoma mansoni Histone Deacetylase 8 (HDAC8) Inhibitors Identified by Structure-Based Virtual Screening and In Vitro Testing
JF - Molecules
VL - 23
IS - 3
SP - 1-14
EP - 1-14
PB - Mayer und Muller
SN - 14203049
KW - epigenetics
KW - crystal structure
KW - docking
KW - histone deacetylase (HDAC) inhibitors
KW - schistosomiasis
KW - virtual screening
UR - https://www.mdpi.com/1420-3049/23/3/566
L2 - https://www.mdpi.com/1420-3049/23/3/566
N2 - A promising means in the search of new small molecules for the treatment of schistosomiasis (amongst other parasitic ailments) is by targeting the parasitic epigenome. In the present study, a docking based virtual screening procedure using the crystal structure of histone deacetylase 8 from Schistosoma mansoni (smHDAC8) was designed. From the developed screening protocol, we were able to identify eight novel N-(2,5-dioxopyrrolidin-3-yl)-n-alkylhydroxamate derivatives as smHDAC8 inhibitors with IC50 values ranging from 4.4-20.3 mu M against smHDAC8. These newly identified inhibitors were further tested against human histone deacetylases (hsHDAC1, 6 and 8), and were found also to be exerting interesting activity against them. In silico prediction of the docking pose of the compounds was confirmed by the resolved crystal structure of one of the identified hits. This confirmed these compounds were able to chelate the catalytic zinc ion in a bidentate fashion, whilst showing an inverted binding mode of the hydroxamate group when compared to the reported smHDAC8/hydroxamates crystal structures. Therefore, they can be considered as new potential scaffold for the development of new smHDAC8 inhibitors by further investigation of their structure-activity relationship.
ER -
SIMOBEN, Conrad V., Dina ROBAA, Alokta CHAKRABARTI, Karin SCHMIDTKUNZ, Martin MAREK, Julien LANCELOT, Srinivasaraghavan KANNAN, Jelena MELESINA, Tajith B. SHAIK, Raymond J. PIERCE, Christophe ROMIER, Manfred JUNG a Wolfgang SIPPL. A Novel Class of Schistosoma mansoni Histone Deacetylase 8 (HDAC8) Inhibitors Identified by Structure-Based Virtual Screening and In Vitro Testing. \textit{Molecules}. BASEL: Mayer und Muller, 2018, roč.~23, č.~3, s.~1-14. ISSN~1420-3049. Dostupné z: https://dx.doi.org/10.3390/molecules23030566.
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