Combined molecular dynamics and virtual screening studies to identify novel sirtuin 2 inhibitors
Апстракт
Sirtuins are highly conserved class of NAD+-dependent lysine deacetylases. Altered function of sirtuin 2 (Sirt2)
is related to pathogenesis of cancer, inflammation and neurodegeneration, which makes Sirt2 very attractive drug
target in novel epigenetic research [1]. A number of Sirt2 inhibitors have been recently developed, but for most
of them are missing structural information of their interaction with the enzyme [2, 3]. Our molecular dynamic
(MD) study was performed on recently resolved crystal structures of selective ligand-Sirt2 complexes [1]. In the
MD study were defined significant interactions with novel inhibitors, one of key residues responsible for
conformational stability of cofactor-binding pocket, and residue acting as gate-keeper for cofactor-binding loop.
Some residues completely changed orientation after the MD simulation, compared to the starting crystal
structures. This result indicates on the errors in the X-ray structures that may have influence on structur...e-based
design of novel inhibitors. After clustering of MD trajectory, 20 conformations (centroids) from 20 clusters of
Sirt2 have been selected as representative conformations for retrospective structure based virtual screening. The
virtual screening performances were significantly improved by use of the ensemble of conformations, selected
with this MD methodology, compared to screening against available X-ray structures.
Извор:
EFMC-ISMC, XXV EFMC International Symposium on Medicinal Chemistry, Book of Abstract, 2018, 305-305Издавач:
- Section for Medicinal Chemistry of the Slovenian Pharmaceutical Society
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)
Напомена:
- XXV EFMC International Symposium on Medicinal Chemistry, Ljubljana, Slovenia, September 2-6, 2018
Институција/група
PharmacyTY - CONF AU - Đoković, Nemanja AU - Nikolić, Katarina AU - Lahtela‐Kakkonen, Maija AU - Agbaba, Danica PY - 2018 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4893 AB - Sirtuins are highly conserved class of NAD+-dependent lysine deacetylases. Altered function of sirtuin 2 (Sirt2) is related to pathogenesis of cancer, inflammation and neurodegeneration, which makes Sirt2 very attractive drug target in novel epigenetic research [1]. A number of Sirt2 inhibitors have been recently developed, but for most of them are missing structural information of their interaction with the enzyme [2, 3]. Our molecular dynamic (MD) study was performed on recently resolved crystal structures of selective ligand-Sirt2 complexes [1]. In the MD study were defined significant interactions with novel inhibitors, one of key residues responsible for conformational stability of cofactor-binding pocket, and residue acting as gate-keeper for cofactor-binding loop. Some residues completely changed orientation after the MD simulation, compared to the starting crystal structures. This result indicates on the errors in the X-ray structures that may have influence on structure-based design of novel inhibitors. After clustering of MD trajectory, 20 conformations (centroids) from 20 clusters of Sirt2 have been selected as representative conformations for retrospective structure based virtual screening. The virtual screening performances were significantly improved by use of the ensemble of conformations, selected with this MD methodology, compared to screening against available X-ray structures. PB - Section for Medicinal Chemistry of the Slovenian Pharmaceutical Society C3 - EFMC-ISMC, XXV EFMC International Symposium on Medicinal Chemistry, Book of Abstract T1 - Combined molecular dynamics and virtual screening studies to identify novel sirtuin 2 inhibitors SP - 305 EP - 305 UR - https://hdl.handle.net/21.15107/rcub_farfar_4893 ER -
@conference{ author = "Đoković, Nemanja and Nikolić, Katarina and Lahtela‐Kakkonen, Maija and Agbaba, Danica", year = "2018", abstract = "Sirtuins are highly conserved class of NAD+-dependent lysine deacetylases. Altered function of sirtuin 2 (Sirt2) is related to pathogenesis of cancer, inflammation and neurodegeneration, which makes Sirt2 very attractive drug target in novel epigenetic research [1]. A number of Sirt2 inhibitors have been recently developed, but for most of them are missing structural information of their interaction with the enzyme [2, 3]. Our molecular dynamic (MD) study was performed on recently resolved crystal structures of selective ligand-Sirt2 complexes [1]. In the MD study were defined significant interactions with novel inhibitors, one of key residues responsible for conformational stability of cofactor-binding pocket, and residue acting as gate-keeper for cofactor-binding loop. Some residues completely changed orientation after the MD simulation, compared to the starting crystal structures. This result indicates on the errors in the X-ray structures that may have influence on structure-based design of novel inhibitors. After clustering of MD trajectory, 20 conformations (centroids) from 20 clusters of Sirt2 have been selected as representative conformations for retrospective structure based virtual screening. The virtual screening performances were significantly improved by use of the ensemble of conformations, selected with this MD methodology, compared to screening against available X-ray structures.", publisher = "Section for Medicinal Chemistry of the Slovenian Pharmaceutical Society", journal = "EFMC-ISMC, XXV EFMC International Symposium on Medicinal Chemistry, Book of Abstract", title = "Combined molecular dynamics and virtual screening studies to identify novel sirtuin 2 inhibitors", pages = "305-305", url = "https://hdl.handle.net/21.15107/rcub_farfar_4893" }
Đoković, N., Nikolić, K., Lahtela‐Kakkonen, M.,& Agbaba, D.. (2018). Combined molecular dynamics and virtual screening studies to identify novel sirtuin 2 inhibitors. in EFMC-ISMC, XXV EFMC International Symposium on Medicinal Chemistry, Book of Abstract Section for Medicinal Chemistry of the Slovenian Pharmaceutical Society., 305-305. https://hdl.handle.net/21.15107/rcub_farfar_4893
Đoković N, Nikolić K, Lahtela‐Kakkonen M, Agbaba D. Combined molecular dynamics and virtual screening studies to identify novel sirtuin 2 inhibitors. in EFMC-ISMC, XXV EFMC International Symposium on Medicinal Chemistry, Book of Abstract. 2018;:305-305. https://hdl.handle.net/21.15107/rcub_farfar_4893 .
Đoković, Nemanja, Nikolić, Katarina, Lahtela‐Kakkonen, Maija, Agbaba, Danica, "Combined molecular dynamics and virtual screening studies to identify novel sirtuin 2 inhibitors" in EFMC-ISMC, XXV EFMC International Symposium on Medicinal Chemistry, Book of Abstract (2018):305-305, https://hdl.handle.net/21.15107/rcub_farfar_4893 .