TY  - CONF
AU  - Đoković, Nemanja
AU  - Ilić, Aleksandra
AU  - Čebzan, Alen
AU  - Radović, Branko
AU  - Ružić, Dušan
AU  - Đurić, Ana
AU  - Srdić-Rajić, Tatjana
AU  - Nikolić, Katarina
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5001
AB  - Pancreatic ductal adenocarcinoma (PDAC) ranks among the most formidable and deadly
types of cancer. The emergence of chemoresistance in PDAC plays a significant role in the
unfavorable survival rates, making it imperative to swiftly develop new pharmaceutical
strategies to address this issue and improve treatment outcomes for PDAC (1). Considering
the numerous epigenetic changes observed in PDAC, the utilization of epigenetic drugs,
such as histone deacetylase (HDAC) inhibitors, holds a great promise as a transformative
approach, particularly when used in combination therapy settings (2).
In this study, we investigated the potential of utilizing drug sensitivity data and the basal
gene expression of pancreatic carcinoma cell lines to develop a bioinformatics screening
protocol for prediction of the combinatorial options available for HDAC inhibitors, including
sirtuin (SIRT) inhibitors. Experimental validation of the protocol performed on the two
pancreatic carcinoma cell lines (MIA PaCa-2 cells and PANC-1) confirmed the identified
synergisms between HDAC inhibitors and sphingosine 1-phosphate (S1P) receptor agonist
– fingolimod, or HDAC inhibitors and Rho-associated protein kinase (ROCK) inhibitor – RKI1447 (3).
Developed bioinformatics screening protocol for predictions of synergistic drug
combinations in PDAC identified several previously unreported interaction partners of
HDAC inhibitors. Predicted interaction partners of HDAC inhibitors including Aurora Kinase
A (AURKA) inhibitor, glutaminase (GLS) inhibitor and WEE1 kinase inhibitor were selected
for the design of novel classes of dual-acting HDAC inhibitors by the means of structure-based molecular modelling. Novel dual inhibitors (SIRT/AURKA, HDAC/GLS and HDAC/WEE1)
were designed relying on the known pharmacophoric features and molecular docking
models developed for each of the targets of interest. The docking scores of the designed
inhibitors revealed a notable affinity towards the specific targets. Additionally, when
combined with predictions of drug synergy, these designed molecules exhibit great
potential as promising structures for subsequent experimental evaluation.
PB  - International Association of Physical Chemists
C3  - 10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6
T1  - Towards the multitarget HDAC Inhibitors for the treatment of pancreatic carcinoma by joining the drug synergy predictions and the molecular modeling
SP  - 47
EP  - 47
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5001
ER  - 

@conference{
author = "Đoković, Nemanja and Ilić, Aleksandra and Čebzan, Alen and Radović, Branko and Ružić, Dušan and Đurić, Ana and Srdić-Rajić, Tatjana and Nikolić, Katarina",
year = "2023",
abstract = "Pancreatic ductal adenocarcinoma (PDAC) ranks among the most formidable and deadly
types of cancer. The emergence of chemoresistance in PDAC plays a significant role in the
unfavorable survival rates, making it imperative to swiftly develop new pharmaceutical
strategies to address this issue and improve treatment outcomes for PDAC (1). Considering
the numerous epigenetic changes observed in PDAC, the utilization of epigenetic drugs,
such as histone deacetylase (HDAC) inhibitors, holds a great promise as a transformative
approach, particularly when used in combination therapy settings (2).
In this study, we investigated the potential of utilizing drug sensitivity data and the basal
gene expression of pancreatic carcinoma cell lines to develop a bioinformatics screening
protocol for prediction of the combinatorial options available for HDAC inhibitors, including
sirtuin (SIRT) inhibitors. Experimental validation of the protocol performed on the two
pancreatic carcinoma cell lines (MIA PaCa-2 cells and PANC-1) confirmed the identified
synergisms between HDAC inhibitors and sphingosine 1-phosphate (S1P) receptor agonist
– fingolimod, or HDAC inhibitors and Rho-associated protein kinase (ROCK) inhibitor – RKI1447 (3).
Developed bioinformatics screening protocol for predictions of synergistic drug
combinations in PDAC identified several previously unreported interaction partners of
HDAC inhibitors. Predicted interaction partners of HDAC inhibitors including Aurora Kinase
A (AURKA) inhibitor, glutaminase (GLS) inhibitor and WEE1 kinase inhibitor were selected
for the design of novel classes of dual-acting HDAC inhibitors by the means of structure-based molecular modelling. Novel dual inhibitors (SIRT/AURKA, HDAC/GLS and HDAC/WEE1)
were designed relying on the known pharmacophoric features and molecular docking
models developed for each of the targets of interest. The docking scores of the designed
inhibitors revealed a notable affinity towards the specific targets. Additionally, when
combined with predictions of drug synergy, these designed molecules exhibit great
potential as promising structures for subsequent experimental evaluation.",
publisher = "International Association of Physical Chemists",
journal = "10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6",
title = "Towards the multitarget HDAC Inhibitors for the treatment of pancreatic carcinoma by joining the drug synergy predictions and the molecular modeling",
pages = "47-47",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5001"
}

Đoković, N., Ilić, A., Čebzan, A., Radović, B., Ružić, D., Đurić, A., Srdić-Rajić, T.,& Nikolić, K.. (2023). Towards the multitarget HDAC Inhibitors for the treatment of pancreatic carcinoma by joining the drug synergy predictions and the molecular modeling. in 10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6
International Association of Physical Chemists., 47-47.
https://hdl.handle.net/21.15107/rcub_farfar_5001

Đoković N, Ilić A, Čebzan A, Radović B, Ružić D, Đurić A, Srdić-Rajić T, Nikolić K. Towards the multitarget HDAC Inhibitors for the treatment of pancreatic carcinoma by joining the drug synergy predictions and the molecular modeling. in 10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6. 2023;:47-47.
https://hdl.handle.net/21.15107/rcub_farfar_5001 .

Đoković, Nemanja, Ilić, Aleksandra, Čebzan, Alen, Radović, Branko, Ružić, Dušan, Đurić, Ana, Srdić-Rajić, Tatjana, Nikolić, Katarina, "Towards the multitarget HDAC Inhibitors for the treatment of pancreatic carcinoma by joining the drug synergy predictions and the molecular modeling" in 10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6 (2023):47-47,
https://hdl.handle.net/21.15107/rcub_farfar_5001 .

TY  - CONF
AU  - Čebzan, Alen
AU  - Ružić, Dušan
AU  - Nikolić, Katarina
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4952
PB  - European Association for Cancer Research
C3  - EACR-Boehringer Ingelheim Drugging and Regulating the MAP Kinase Pathway Virtual Event, Worldwide : 21 - 22 February 2023
T1  - Computer-aided drug design of MAPK inhibitors by combined 3D-QSAR analysis and molecular docking
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4952
ER  - 

@conference{
author = "Čebzan, Alen and Ružić, Dušan and Nikolić, Katarina",
year = "2023",
publisher = "European Association for Cancer Research",
journal = "EACR-Boehringer Ingelheim Drugging and Regulating the MAP Kinase Pathway Virtual Event, Worldwide : 21 - 22 February 2023",
title = "Computer-aided drug design of MAPK inhibitors by combined 3D-QSAR analysis and molecular docking",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4952"
}

Čebzan, A., Ružić, D.,& Nikolić, K.. (2023). Computer-aided drug design of MAPK inhibitors by combined 3D-QSAR analysis and molecular docking. in EACR-Boehringer Ingelheim Drugging and Regulating the MAP Kinase Pathway Virtual Event, Worldwide : 21 - 22 February 2023
European Association for Cancer Research..
https://hdl.handle.net/21.15107/rcub_farfar_4952

Čebzan A, Ružić D, Nikolić K. Computer-aided drug design of MAPK inhibitors by combined 3D-QSAR analysis and molecular docking. in EACR-Boehringer Ingelheim Drugging and Regulating the MAP Kinase Pathway Virtual Event, Worldwide : 21 - 22 February 2023. 2023;.
https://hdl.handle.net/21.15107/rcub_farfar_4952 .

Čebzan, Alen, Ružić, Dušan, Nikolić, Katarina, "Computer-aided drug design of MAPK inhibitors by combined 3D-QSAR analysis and molecular docking" in EACR-Boehringer Ingelheim Drugging and Regulating the MAP Kinase Pathway Virtual Event, Worldwide : 21 - 22 February 2023 (2023),
https://hdl.handle.net/21.15107/rcub_farfar_4952 .

TY  - CONF
AU  - Čebzan, Alen
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4149
AB  - Митоген-активирана протеин киназа 1 (MAPK1) представља серин-треонин киназу која учествује у сигналној трансдукцији помоћу Ras/Raf/MEK/ERK каскадног пута. Познато је да хумане туморске ћелије могу имати прекомерно експримиран ниво MAPK1, те је ово један од значајних циљних места развоја нових антиканцерских лекова.
AB  - Mitogen-activated protein kinase 1 (MAPK1) presents serine-threonine kinase which is included in signal transduction throught Ras/Raf/MEK/ERK cascade. Human tumor cells may have overexpressed MAPK1 level, so this enzyme is an important target for designing new antitumor drugs.
T1  - Компјутерски дизајн нових MAPK инхибитора компаративном анализом резултата 3D-QSAR моделовања и молекулског докинга
T1  - Computer-aided design of new MAPK inhibitors by comparative analysis of 3D-QSAR modeling and molecular docking results
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4149
ER  - 

@conference{
author = "Čebzan, Alen",
year = "2022",
abstract = "Митоген-активирана протеин киназа 1 (MAPK1) представља серин-треонин киназу која учествује у сигналној трансдукцији помоћу Ras/Raf/MEK/ERK каскадног пута. Познато је да хумане туморске ћелије могу имати прекомерно експримиран ниво MAPK1, те је ово један од значајних циљних места развоја нових антиканцерских лекова., Mitogen-activated protein kinase 1 (MAPK1) presents serine-threonine kinase which is included in signal transduction throught Ras/Raf/MEK/ERK cascade. Human tumor cells may have overexpressed MAPK1 level, so this enzyme is an important target for designing new antitumor drugs.",
title = "Компјутерски дизајн нових MAPK инхибитора компаративном анализом резултата 3D-QSAR моделовања и молекулског докинга, Computer-aided design of new MAPK inhibitors by comparative analysis of 3D-QSAR modeling and molecular docking results",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4149"
}

Čebzan, A.. (2022). Компјутерски дизајн нових MAPK инхибитора компаративном анализом резултата 3D-QSAR моделовања и молекулског докинга. .
https://hdl.handle.net/21.15107/rcub_farfar_4149

Čebzan A. Компјутерски дизајн нових MAPK инхибитора компаративном анализом резултата 3D-QSAR моделовања и молекулског докинга. 2022;.
https://hdl.handle.net/21.15107/rcub_farfar_4149 .

Čebzan, Alen, "Компјутерски дизајн нових MAPK инхибитора компаративном анализом резултата 3D-QSAR моделовања и молекулског докинга" (2022),
https://hdl.handle.net/21.15107/rcub_farfar_4149 .

TY  - CONF
AU  - Ružić, Dušan
AU  - Čebzan, Alen
AU  - Nikolić, Katarina
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4854
AB  - Three different classes of mitogen-activated protein kinase 1 (MAPK1)
inhibitors (derivatives of pyrimidine-pyridone, acetamidothiazole and
pyrazolyl-pyrrole) were used to perform three-dimensional Quantitative
Structure-Activity Relationship (3D-QSAR) study. The number of 92 MAPK1
inhibitors, split into training and test sets, was extracted from ChEMBL
database, with their enzymatic inhibitory constants determined on human
MAPK1. The statistically significant 3D-QSAR models were further
validated. The 3D-QSAR model with the best statistical and validation
parameters was further used to define main structural determinant for efficient
inhibition of MAPK1 enzyme.
PB  - Society of Physical Chemists of Serbia
C3  - Physical Chemistry 2018 (Proceedings) 14th International Conference on Fundamental and Applied Aspects of Physical Chemistry
T1  - A 3D-QSAR study on a set of MAPK1 inhibitors
VL  - I
SP  - 101
EP  - 104
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4854
ER  - 

@conference{
author = "Ružić, Dušan and Čebzan, Alen and Nikolić, Katarina",
year = "2018",
abstract = "Three different classes of mitogen-activated protein kinase 1 (MAPK1)
inhibitors (derivatives of pyrimidine-pyridone, acetamidothiazole and
pyrazolyl-pyrrole) were used to perform three-dimensional Quantitative
Structure-Activity Relationship (3D-QSAR) study. The number of 92 MAPK1
inhibitors, split into training and test sets, was extracted from ChEMBL
database, with their enzymatic inhibitory constants determined on human
MAPK1. The statistically significant 3D-QSAR models were further
validated. The 3D-QSAR model with the best statistical and validation
parameters was further used to define main structural determinant for efficient
inhibition of MAPK1 enzyme.",
publisher = "Society of Physical Chemists of Serbia",
journal = "Physical Chemistry 2018 (Proceedings) 14th International Conference on Fundamental and Applied Aspects of Physical Chemistry",
title = "A 3D-QSAR study on a set of MAPK1 inhibitors",
volume = "I",
pages = "101-104",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4854"
}

Ružić, D., Čebzan, A.,& Nikolić, K.. (2018). A 3D-QSAR study on a set of MAPK1 inhibitors. in Physical Chemistry 2018 (Proceedings) 14th International Conference on Fundamental and Applied Aspects of Physical Chemistry
Society of Physical Chemists of Serbia., I, 101-104.
https://hdl.handle.net/21.15107/rcub_farfar_4854

Ružić D, Čebzan A, Nikolić K. A 3D-QSAR study on a set of MAPK1 inhibitors. in Physical Chemistry 2018 (Proceedings) 14th International Conference on Fundamental and Applied Aspects of Physical Chemistry. 2018;I:101-104.
https://hdl.handle.net/21.15107/rcub_farfar_4854 .

Ružić, Dušan, Čebzan, Alen, Nikolić, Katarina, "A 3D-QSAR study on a set of MAPK1 inhibitors" in Physical Chemistry 2018 (Proceedings) 14th International Conference on Fundamental and Applied Aspects of Physical Chemistry, I (2018):101-104,
https://hdl.handle.net/21.15107/rcub_farfar_4854 .