A theoretical study of interaction between HDAC-1 and HDAC-6 enzymes and in silico designed inhibitors
Teorijsko proučavanje interakcija između HDAC-1 i HDAC-6 enzima i in silico dizajniranih inhibitora
Konferencijski prilog (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
The disproportionate posttranslational histone modification as deacetylation has been associated with tumorigenesis and neurodegenerative diseases. Currently, there are five approved histone deacetylase (HDAC) inhibitors by FDA, which are defined as pan-HDAC inhibitors. By using ligand based virtual design approach (3D-QSAR) based on naphthalimide derivative scriptaid, we found molecular determinants important for selectivity towards histone deacetylase 6 isoform. After in silico design of novel inhibitors, we performed molecular docking studies using crystal structure of HDAC-1 enzyme (5ICN) and crystal structure of second human catalytic domain of HDAC-6 enzyme (5EDU). Molecular docking procedure was performed in GOLD 5.4.0 Software and ChemScore as scoring functions, and two in silico designed compounds D-48 and D-34 were selected as potential selective HDAC-6 inhibitors for synthesis. The shorter linker of selected compounds allows hydroxamic group to be more accessible to Zn2+ ion... at the bottom of the active pocket. Both of them shown improved predicted selectivity according to the developed 3D-QSAR models.
Nesrazmerna posttranslaciona deacetilacija histona je povezana sa nastankom tumora i
neurodegenerativnim bolestima. Do sada, FDA je registrovala 5 inhibitora histon deacetilaze
(HDAC), koji su okarakterisani kao neselektivni HDAC inhibitori. Koristeći virtuelni dizajn
zasnovan na hemijskoj strukturi liganda (3D-QSAR), na primeru naftalimidnog derivata
skriptaida, utvrdili smo molekulske karakteristike značajne za selektivnu inhibiciju histon
deacetilaze 6. Nakon in silico dizajna novih inhibitora, primenili smo molekulski doking koristeći
kristalnu strukturu HDAC-1 enzima (5ICN) i kristalnu strukturu drugog katalitičkog domena
HDAC-6 enzima (5EDU). Molekulski doking je proučavan u GOLD 5.4.0 softveru, koristeći
ChemScore kao skoring funkciju, i dva in silico dizajnirana jedinjenja D-48 I D-34 su odabrana kao
potencijalni selektivni HDAC-6 inhibitori za sintezu. Kraći linker odabranih jedinjenja omogućuje
hidroksamskoj grupi da bude dostupnija Zn2+ jonu pri dnu aktivnog mesta ...enzima. Oba jedinjenja
su pokazala poboljšanu selektivnost predviđenu razvijenim 3D-QSAR modelima.
Izvor:
Fourth Conference of Young Chemists of Serbia, Belgrade, Serbia, November 5, 2016, 2016, 101-101Izdavač:
- Serbian Chemical Society and Serbian Young Chemists’ Club
Finansiranje / projekti:
- Sinteza, kvantitativni odnos između strukture i dejstva, fizičko-hemijska karakterizacija i analiza farmakološki aktivnih supstanci (RS-MESTD-Basic Research (BR or ON)-172033)
Napomena:
- Book of Abstracts - Fourth Conference of Young Chemists of Serbia Belgrade, November 5, 2016
Institucija/grupa
PharmacyTY - CONF AU - Ružić, Dušan AU - Nikolić, Katarina AU - Agbaba, Danica PY - 2016 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4925 AB - The disproportionate posttranslational histone modification as deacetylation has been associated with tumorigenesis and neurodegenerative diseases. Currently, there are five approved histone deacetylase (HDAC) inhibitors by FDA, which are defined as pan-HDAC inhibitors. By using ligand based virtual design approach (3D-QSAR) based on naphthalimide derivative scriptaid, we found molecular determinants important for selectivity towards histone deacetylase 6 isoform. After in silico design of novel inhibitors, we performed molecular docking studies using crystal structure of HDAC-1 enzyme (5ICN) and crystal structure of second human catalytic domain of HDAC-6 enzyme (5EDU). Molecular docking procedure was performed in GOLD 5.4.0 Software and ChemScore as scoring functions, and two in silico designed compounds D-48 and D-34 were selected as potential selective HDAC-6 inhibitors for synthesis. The shorter linker of selected compounds allows hydroxamic group to be more accessible to Zn2+ ion at the bottom of the active pocket. Both of them shown improved predicted selectivity according to the developed 3D-QSAR models. AB - Nesrazmerna posttranslaciona deacetilacija histona je povezana sa nastankom tumora i neurodegenerativnim bolestima. Do sada, FDA je registrovala 5 inhibitora histon deacetilaze (HDAC), koji su okarakterisani kao neselektivni HDAC inhibitori. Koristeći virtuelni dizajn zasnovan na hemijskoj strukturi liganda (3D-QSAR), na primeru naftalimidnog derivata skriptaida, utvrdili smo molekulske karakteristike značajne za selektivnu inhibiciju histon deacetilaze 6. Nakon in silico dizajna novih inhibitora, primenili smo molekulski doking koristeći kristalnu strukturu HDAC-1 enzima (5ICN) i kristalnu strukturu drugog katalitičkog domena HDAC-6 enzima (5EDU). Molekulski doking je proučavan u GOLD 5.4.0 softveru, koristeći ChemScore kao skoring funkciju, i dva in silico dizajnirana jedinjenja D-48 I D-34 su odabrana kao potencijalni selektivni HDAC-6 inhibitori za sintezu. Kraći linker odabranih jedinjenja omogućuje hidroksamskoj grupi da bude dostupnija Zn2+ jonu pri dnu aktivnog mesta enzima. Oba jedinjenja su pokazala poboljšanu selektivnost predviđenu razvijenim 3D-QSAR modelima. PB - Serbian Chemical Society and Serbian Young Chemists’ Club C3 - Fourth Conference of Young Chemists of Serbia, Belgrade, Serbia, November 5, 2016 T1 - A theoretical study of interaction between HDAC-1 and HDAC-6 enzymes and in silico designed inhibitors T1 - Teorijsko proučavanje interakcija između HDAC-1 i HDAC-6 enzima i in silico dizajniranih inhibitora SP - 101 EP - 101 UR - https://hdl.handle.net/21.15107/rcub_farfar_4925 ER -
@conference{ author = "Ružić, Dušan and Nikolić, Katarina and Agbaba, Danica", year = "2016", abstract = "The disproportionate posttranslational histone modification as deacetylation has been associated with tumorigenesis and neurodegenerative diseases. Currently, there are five approved histone deacetylase (HDAC) inhibitors by FDA, which are defined as pan-HDAC inhibitors. By using ligand based virtual design approach (3D-QSAR) based on naphthalimide derivative scriptaid, we found molecular determinants important for selectivity towards histone deacetylase 6 isoform. After in silico design of novel inhibitors, we performed molecular docking studies using crystal structure of HDAC-1 enzyme (5ICN) and crystal structure of second human catalytic domain of HDAC-6 enzyme (5EDU). Molecular docking procedure was performed in GOLD 5.4.0 Software and ChemScore as scoring functions, and two in silico designed compounds D-48 and D-34 were selected as potential selective HDAC-6 inhibitors for synthesis. The shorter linker of selected compounds allows hydroxamic group to be more accessible to Zn2+ ion at the bottom of the active pocket. Both of them shown improved predicted selectivity according to the developed 3D-QSAR models., Nesrazmerna posttranslaciona deacetilacija histona je povezana sa nastankom tumora i neurodegenerativnim bolestima. Do sada, FDA je registrovala 5 inhibitora histon deacetilaze (HDAC), koji su okarakterisani kao neselektivni HDAC inhibitori. Koristeći virtuelni dizajn zasnovan na hemijskoj strukturi liganda (3D-QSAR), na primeru naftalimidnog derivata skriptaida, utvrdili smo molekulske karakteristike značajne za selektivnu inhibiciju histon deacetilaze 6. Nakon in silico dizajna novih inhibitora, primenili smo molekulski doking koristeći kristalnu strukturu HDAC-1 enzima (5ICN) i kristalnu strukturu drugog katalitičkog domena HDAC-6 enzima (5EDU). Molekulski doking je proučavan u GOLD 5.4.0 softveru, koristeći ChemScore kao skoring funkciju, i dva in silico dizajnirana jedinjenja D-48 I D-34 su odabrana kao potencijalni selektivni HDAC-6 inhibitori za sintezu. Kraći linker odabranih jedinjenja omogućuje hidroksamskoj grupi da bude dostupnija Zn2+ jonu pri dnu aktivnog mesta enzima. Oba jedinjenja su pokazala poboljšanu selektivnost predviđenu razvijenim 3D-QSAR modelima.", publisher = "Serbian Chemical Society and Serbian Young Chemists’ Club", journal = "Fourth Conference of Young Chemists of Serbia, Belgrade, Serbia, November 5, 2016", title = "A theoretical study of interaction between HDAC-1 and HDAC-6 enzymes and in silico designed inhibitors, Teorijsko proučavanje interakcija između HDAC-1 i HDAC-6 enzima i in silico dizajniranih inhibitora", pages = "101-101", url = "https://hdl.handle.net/21.15107/rcub_farfar_4925" }
Ružić, D., Nikolić, K.,& Agbaba, D.. (2016). A theoretical study of interaction between HDAC-1 and HDAC-6 enzymes and in silico designed inhibitors. in Fourth Conference of Young Chemists of Serbia, Belgrade, Serbia, November 5, 2016 Serbian Chemical Society and Serbian Young Chemists’ Club., 101-101. https://hdl.handle.net/21.15107/rcub_farfar_4925
Ružić D, Nikolić K, Agbaba D. A theoretical study of interaction between HDAC-1 and HDAC-6 enzymes and in silico designed inhibitors. in Fourth Conference of Young Chemists of Serbia, Belgrade, Serbia, November 5, 2016. 2016;:101-101. https://hdl.handle.net/21.15107/rcub_farfar_4925 .
Ružić, Dušan, Nikolić, Katarina, Agbaba, Danica, "A theoretical study of interaction between HDAC-1 and HDAC-6 enzymes and in silico designed inhibitors" in Fourth Conference of Young Chemists of Serbia, Belgrade, Serbia, November 5, 2016 (2016):101-101, https://hdl.handle.net/21.15107/rcub_farfar_4925 .