Computer-aided drug design of selective histone deacetylase inhibitors
Аутори
Nikolić, KatarinaRužić, Dušan
Đoković, Nemanja
Petković, Miloš
Agbaba, Danica
Lahtela-Kakkonen, Maija
Ganesan, A.
Конференцијски прилог (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
The concept of gene expression is continuously explained with epigenetic modification. Post-translational histone acetylation and DNA methylation are dominant epigenetic alterations of the genome. Histone deacetylases (HDAC) play essential role in this process and therefore are very intensively investigated drug targets. The alteration in the structure and function of HDAC isoforms are identified in the pathogenesis of inflammation, cancer, and neurodegeneration. Eleven human HDAC isoforms are sharing a highly conserved catalytic domain. Among them, HDAC6 and SIRT2 are important for a wide range of diseases, due to their unique physiological functions. In our research, we have applied pharmacophore modelling, virtual screening, molecular docking and molecular dynamic methodologies for design and identification of selective HDAC6 and SIRT2 inhibitors. Recently resolved the crystal structure of catalytic domain II of human HDAC6 discovered a wide binding site essential for the substrate ...recognition. We have successfully used these structural features of human HDAC6 catalytic domain II to rationally design selective HDAC6 inhibitors. Newly published X-ray structures of selective ligand-SIRT2 complexes have revealed high conformational flexibility of this enzyme, and gave us more details about mechanism of action of sirtuin 2 inhibitors. Based on these findings we have performed molecular dynamic study of SIRT2 and tried to explain the conformational changes during enzyme catalysis. Since small number of selective HDAC modulators have been reported so far, rational design of HDAC6 and SIRT2 inhibitors are essential for further progress in discovery of epigenetic drugs.
Извор:
Journal of organic & inorganic chemistry, 2018, 28-28Издавач:
- iMedPub LTD
Финансирање / пројекти:
- Синтеза, квантитативни однос између структуре и дејства, физичко-хемијска карактеризација и анализа фармаколошки активних супстанци (RS-MESTD-Basic Research (BR or ON)-172033)
- COST Action Epigenetic Chemical Biology CM1406
Напомена:
- European Congress on Advanced Chemistry July 12-13, 2018 Paris, France
Институција/група
PharmacyTY - CONF AU - Nikolić, Katarina AU - Ružić, Dušan AU - Đoković, Nemanja AU - Petković, Miloš AU - Agbaba, Danica AU - Lahtela-Kakkonen, Maija AU - Ganesan, A. PY - 2018 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4929 AB - The concept of gene expression is continuously explained with epigenetic modification. Post-translational histone acetylation and DNA methylation are dominant epigenetic alterations of the genome. Histone deacetylases (HDAC) play essential role in this process and therefore are very intensively investigated drug targets. The alteration in the structure and function of HDAC isoforms are identified in the pathogenesis of inflammation, cancer, and neurodegeneration. Eleven human HDAC isoforms are sharing a highly conserved catalytic domain. Among them, HDAC6 and SIRT2 are important for a wide range of diseases, due to their unique physiological functions. In our research, we have applied pharmacophore modelling, virtual screening, molecular docking and molecular dynamic methodologies for design and identification of selective HDAC6 and SIRT2 inhibitors. Recently resolved the crystal structure of catalytic domain II of human HDAC6 discovered a wide binding site essential for the substrate recognition. We have successfully used these structural features of human HDAC6 catalytic domain II to rationally design selective HDAC6 inhibitors. Newly published X-ray structures of selective ligand-SIRT2 complexes have revealed high conformational flexibility of this enzyme, and gave us more details about mechanism of action of sirtuin 2 inhibitors. Based on these findings we have performed molecular dynamic study of SIRT2 and tried to explain the conformational changes during enzyme catalysis. Since small number of selective HDAC modulators have been reported so far, rational design of HDAC6 and SIRT2 inhibitors are essential for further progress in discovery of epigenetic drugs. PB - iMedPub LTD C3 - Journal of organic & inorganic chemistry T1 - Computer-aided drug design of selective histone deacetylase inhibitors SP - 28 EP - 28 DO - 10.21767/2472-1123-C2-005 ER -
@conference{ author = "Nikolić, Katarina and Ružić, Dušan and Đoković, Nemanja and Petković, Miloš and Agbaba, Danica and Lahtela-Kakkonen, Maija and Ganesan, A.", year = "2018", abstract = "The concept of gene expression is continuously explained with epigenetic modification. Post-translational histone acetylation and DNA methylation are dominant epigenetic alterations of the genome. Histone deacetylases (HDAC) play essential role in this process and therefore are very intensively investigated drug targets. The alteration in the structure and function of HDAC isoforms are identified in the pathogenesis of inflammation, cancer, and neurodegeneration. Eleven human HDAC isoforms are sharing a highly conserved catalytic domain. Among them, HDAC6 and SIRT2 are important for a wide range of diseases, due to their unique physiological functions. In our research, we have applied pharmacophore modelling, virtual screening, molecular docking and molecular dynamic methodologies for design and identification of selective HDAC6 and SIRT2 inhibitors. Recently resolved the crystal structure of catalytic domain II of human HDAC6 discovered a wide binding site essential for the substrate recognition. We have successfully used these structural features of human HDAC6 catalytic domain II to rationally design selective HDAC6 inhibitors. Newly published X-ray structures of selective ligand-SIRT2 complexes have revealed high conformational flexibility of this enzyme, and gave us more details about mechanism of action of sirtuin 2 inhibitors. Based on these findings we have performed molecular dynamic study of SIRT2 and tried to explain the conformational changes during enzyme catalysis. Since small number of selective HDAC modulators have been reported so far, rational design of HDAC6 and SIRT2 inhibitors are essential for further progress in discovery of epigenetic drugs.", publisher = "iMedPub LTD", journal = "Journal of organic & inorganic chemistry", title = "Computer-aided drug design of selective histone deacetylase inhibitors", pages = "28-28", doi = "10.21767/2472-1123-C2-005" }
Nikolić, K., Ružić, D., Đoković, N., Petković, M., Agbaba, D., Lahtela-Kakkonen, M.,& Ganesan, A.. (2018). Computer-aided drug design of selective histone deacetylase inhibitors. in Journal of organic & inorganic chemistry iMedPub LTD., 28-28. https://doi.org/10.21767/2472-1123-C2-005
Nikolić K, Ružić D, Đoković N, Petković M, Agbaba D, Lahtela-Kakkonen M, Ganesan A. Computer-aided drug design of selective histone deacetylase inhibitors. in Journal of organic & inorganic chemistry. 2018;:28-28. doi:10.21767/2472-1123-C2-005 .
Nikolić, Katarina, Ružić, Dušan, Đoković, Nemanja, Petković, Miloš, Agbaba, Danica, Lahtela-Kakkonen, Maija, Ganesan, A., "Computer-aided drug design of selective histone deacetylase inhibitors" in Journal of organic & inorganic chemistry (2018):28-28, https://doi.org/10.21767/2472-1123-C2-005 . .