TY  - JOUR
AU  - Cvijetić, Ilija 
AU  - Herlah, Barbara
AU  - Marinković, Aleksandar
AU  - Perdih, Andrej
AU  - Bjelogrlić, Snežana K.
PY  - 2023
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/6246
AB  - Phenotypic screening of α-substituted thiocarbohydrazones revealed promising activity of 1,5-bis(salicylidene)thiocarbohydrazide against leukemia and breast cancer cells. Supplementary cell-based studies indicated an impairment of DNA replication via the ROS-independent pathway. The structural similarity of α-substituted thiocarbohydrazone to previously published thiosemicarbazone catalytic inhibitors targeting the ATP-binding site of human DNA topoisomerase IIα prompted us to investigate the inhibition activity on this target. Thiocarbohydrazone acted as a catalytic inhibitor and did not intercalate the DNA molecule, which validated their engagement with this cancer target. A comprehensive computational assessment of molecular recognition for a selected thiosemicarbazone and thiocarbohydrazone provided useful information for further optimization of this discovered lead compound for chemotherapeutic anticancer drug discovery.
PB  - MDPI
T2  - Pharmaceuticals
T1  - Phenotypic Discovery of Thiocarbohydrazone with Anticancer Properties and Catalytic Inhibition of Human DNA Topoisomerase IIα
VL  - 16
IS  - 3
SP  - 341
DO  - 10.3390/ph16030341
ER  - 

@article{
author = "Cvijetić, Ilija  and Herlah, Barbara and Marinković, Aleksandar and Perdih, Andrej and Bjelogrlić, Snežana K.",
year = "2023",
abstract = "Phenotypic screening of α-substituted thiocarbohydrazones revealed promising activity of 1,5-bis(salicylidene)thiocarbohydrazide against leukemia and breast cancer cells. Supplementary cell-based studies indicated an impairment of DNA replication via the ROS-independent pathway. The structural similarity of α-substituted thiocarbohydrazone to previously published thiosemicarbazone catalytic inhibitors targeting the ATP-binding site of human DNA topoisomerase IIα prompted us to investigate the inhibition activity on this target. Thiocarbohydrazone acted as a catalytic inhibitor and did not intercalate the DNA molecule, which validated their engagement with this cancer target. A comprehensive computational assessment of molecular recognition for a selected thiosemicarbazone and thiocarbohydrazone provided useful information for further optimization of this discovered lead compound for chemotherapeutic anticancer drug discovery.",
publisher = "MDPI",
journal = "Pharmaceuticals",
title = "Phenotypic Discovery of Thiocarbohydrazone with Anticancer Properties and Catalytic Inhibition of Human DNA Topoisomerase IIα",
volume = "16",
number = "3",
pages = "341",
doi = "10.3390/ph16030341"
}

Cvijetić, I., Herlah, B., Marinković, A., Perdih, A.,& Bjelogrlić, S. K.. (2023). Phenotypic Discovery of Thiocarbohydrazone with Anticancer Properties and Catalytic Inhibition of Human DNA Topoisomerase IIα. in Pharmaceuticals
MDPI., 16(3), 341.
https://doi.org/10.3390/ph16030341

Cvijetić I, Herlah B, Marinković A, Perdih A, Bjelogrlić SK. Phenotypic Discovery of Thiocarbohydrazone with Anticancer Properties and Catalytic Inhibition of Human DNA Topoisomerase IIα. in Pharmaceuticals. 2023;16(3):341.
doi:10.3390/ph16030341 .

Cvijetić, Ilija , Herlah, Barbara, Marinković, Aleksandar, Perdih, Andrej, Bjelogrlić, Snežana K., "Phenotypic Discovery of Thiocarbohydrazone with Anticancer Properties and Catalytic Inhibition of Human DNA Topoisomerase IIα" in Pharmaceuticals, 16, no. 3 (2023):341,
https://doi.org/10.3390/ph16030341 . .

TY  - JOUR
AU  - Vitorović-Todorović, Maja D.
AU  - Cvijetić, Ilija
AU  - Zloh, Mire
AU  - Perdih, Andrej
PY  - 2022
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/4979
AB  - Recently, we designed and synthesized a subnanomolar, reversible, dual-binding site acetylcholinesterase (AChE) inhibitor which consists of the tacrine and aroylacrylic acid phenylamide moieties, mutually linked by eight methylene units. To further investigate the process of the molecular recognition between the AChE and its inhibitor, we performed six unconstrained molecular dynamics (MD) simulations, where the compound in three possible protonation states was placed inside binding sites of two available AChE crystal structures. In all six MD trajectories, the ligand generally occupied similar space inside the AChE active site, but the pattern of the interactions between the ligand functional groups and the amino acid residues was significantly different and highly dependent upon the crystal structure used to generate initial systems for simulation. The greatest differences were observed between the trajectories obtained with different AChE crystal structures used as starting target conformations. In some trajectories, several unusual positions and dynamic behavior of the tacrine moiety were observed. Therefore, this study provides important structure-based data useful in further optimization of the reversible, dual binding AChE inhibitors, and also emphasizes the importance of the starting crystal structure used for dynamics as well as the protonation state of the reversible inhibitors.Communicated by Ramaswamy H. Sarma
PB  - Taylor & Francis
T2  - Journal of Biomolecular Structure and Dynamics
T1  - Molecular recognition of acetylcholinesterase and its subnanomolar reversible inhibitor: a molecular simulations study
VL  - 40
IS  - 4
SP  - 1671
EP  - 1691
DO  - 10.1080/07391102.2020.1831960
ER  - 

@article{
author = "Vitorović-Todorović, Maja D. and Cvijetić, Ilija and Zloh, Mire and Perdih, Andrej",
year = "2022",
abstract = "Recently, we designed and synthesized a subnanomolar, reversible, dual-binding site acetylcholinesterase (AChE) inhibitor which consists of the tacrine and aroylacrylic acid phenylamide moieties, mutually linked by eight methylene units. To further investigate the process of the molecular recognition between the AChE and its inhibitor, we performed six unconstrained molecular dynamics (MD) simulations, where the compound in three possible protonation states was placed inside binding sites of two available AChE crystal structures. In all six MD trajectories, the ligand generally occupied similar space inside the AChE active site, but the pattern of the interactions between the ligand functional groups and the amino acid residues was significantly different and highly dependent upon the crystal structure used to generate initial systems for simulation. The greatest differences were observed between the trajectories obtained with different AChE crystal structures used as starting target conformations. In some trajectories, several unusual positions and dynamic behavior of the tacrine moiety were observed. Therefore, this study provides important structure-based data useful in further optimization of the reversible, dual binding AChE inhibitors, and also emphasizes the importance of the starting crystal structure used for dynamics as well as the protonation state of the reversible inhibitors.Communicated by Ramaswamy H. Sarma",
publisher = "Taylor & Francis",
journal = "Journal of Biomolecular Structure and Dynamics",
title = "Molecular recognition of acetylcholinesterase and its subnanomolar reversible inhibitor: a molecular simulations study",
volume = "40",
number = "4",
pages = "1671-1691",
doi = "10.1080/07391102.2020.1831960"
}

Vitorović-Todorović, M. D., Cvijetić, I., Zloh, M.,& Perdih, A.. (2022). Molecular recognition of acetylcholinesterase and its subnanomolar reversible inhibitor: a molecular simulations study. in Journal of Biomolecular Structure and Dynamics
Taylor & Francis., 40(4), 1671-1691.
https://doi.org/10.1080/07391102.2020.1831960

Vitorović-Todorović MD, Cvijetić I, Zloh M, Perdih A. Molecular recognition of acetylcholinesterase and its subnanomolar reversible inhibitor: a molecular simulations study. in Journal of Biomolecular Structure and Dynamics. 2022;40(4):1671-1691.
doi:10.1080/07391102.2020.1831960 .

Vitorović-Todorović, Maja D., Cvijetić, Ilija, Zloh, Mire, Perdih, Andrej, "Molecular recognition of acetylcholinesterase and its subnanomolar reversible inhibitor: a molecular simulations study" in Journal of Biomolecular Structure and Dynamics, 40, no. 4 (2022):1671-1691,
https://doi.org/10.1080/07391102.2020.1831960 . .

TY  - DATA
AU  - Vitorović-Todorović, Maja D.
AU  - Cvijetić, Ilija
AU  - Zloh, Mire
AU  - Perdih, Andrej
PY  - 2022
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/4980
AB  - Recently, we designed and synthesized a subnanomolar, reversible, dual-binding site acetylcholinesterase (AChE) inhibitor which consists of the tacrine and aroylacrylic acid phenylamide moieties, mutually linked by eight methylene units. To further investigate the process of the molecular recognition between the AChE and its inhibitor, we performed six unconstrained molecular dynamics (MD) simulations, where the compound in three possible protonation states was placed inside binding sites of two available AChE crystal structures. In all six MD trajectories, the ligand generally occupied similar space inside the AChE active site, but the pattern of the interactions between the ligand functional groups and the amino acid residues was significantly different and highly dependent upon the crystal structure used to generate initial systems for simulation. The greatest differences were observed between the trajectories obtained with different AChE crystal structures used as starting target conformations. In some trajectories, several unusual positions and dynamic behavior of the tacrine moiety were observed. Therefore, this study provides important structure-based data useful in further optimization of the reversible, dual binding AChE inhibitors, and also emphasizes the importance of the starting crystal structure used for dynamics as well as the protonation state of the reversible inhibitors.
PB  - Taylor & Francis
T2  - Journal of Biomolecular Structure and Dynamics
T1  - Supplementary data for the article: Vitorović-Todorović, M.; Cvijetić, I.; Zloh, M.; Perdih, A. Molecular Recognition of Acetylcholinesterase and Its Subnanomolar Reversible Inhibitor: A Molecular Simulations Study. Journal of Biomolecular Structure and Dynamics 2022, 40 (4), 1671–1691. https://doi.org/10.1080/07391102.2020.1831960.
UR  - https://hdl.handle.net/21.15107/rcub_cherry_4980
ER  - 

@misc{
author = "Vitorović-Todorović, Maja D. and Cvijetić, Ilija and Zloh, Mire and Perdih, Andrej",
year = "2022",
abstract = "Recently, we designed and synthesized a subnanomolar, reversible, dual-binding site acetylcholinesterase (AChE) inhibitor which consists of the tacrine and aroylacrylic acid phenylamide moieties, mutually linked by eight methylene units. To further investigate the process of the molecular recognition between the AChE and its inhibitor, we performed six unconstrained molecular dynamics (MD) simulations, where the compound in three possible protonation states was placed inside binding sites of two available AChE crystal structures. In all six MD trajectories, the ligand generally occupied similar space inside the AChE active site, but the pattern of the interactions between the ligand functional groups and the amino acid residues was significantly different and highly dependent upon the crystal structure used to generate initial systems for simulation. The greatest differences were observed between the trajectories obtained with different AChE crystal structures used as starting target conformations. In some trajectories, several unusual positions and dynamic behavior of the tacrine moiety were observed. Therefore, this study provides important structure-based data useful in further optimization of the reversible, dual binding AChE inhibitors, and also emphasizes the importance of the starting crystal structure used for dynamics as well as the protonation state of the reversible inhibitors.",
publisher = "Taylor & Francis",
journal = "Journal of Biomolecular Structure and Dynamics",
title = "Supplementary data for the article: Vitorović-Todorović, M.; Cvijetić, I.; Zloh, M.; Perdih, A. Molecular Recognition of Acetylcholinesterase and Its Subnanomolar Reversible Inhibitor: A Molecular Simulations Study. Journal of Biomolecular Structure and Dynamics 2022, 40 (4), 1671–1691. https://doi.org/10.1080/07391102.2020.1831960.",
url = "https://hdl.handle.net/21.15107/rcub_cherry_4980"
}

Vitorović-Todorović, M. D., Cvijetić, I., Zloh, M.,& Perdih, A.. (2022). Supplementary data for the article: Vitorović-Todorović, M.; Cvijetić, I.; Zloh, M.; Perdih, A. Molecular Recognition of Acetylcholinesterase and Its Subnanomolar Reversible Inhibitor: A Molecular Simulations Study. Journal of Biomolecular Structure and Dynamics 2022, 40 (4), 1671–1691. https://doi.org/10.1080/07391102.2020.1831960.. in Journal of Biomolecular Structure and Dynamics
Taylor & Francis..
https://hdl.handle.net/21.15107/rcub_cherry_4980

Vitorović-Todorović MD, Cvijetić I, Zloh M, Perdih A. Supplementary data for the article: Vitorović-Todorović, M.; Cvijetić, I.; Zloh, M.; Perdih, A. Molecular Recognition of Acetylcholinesterase and Its Subnanomolar Reversible Inhibitor: A Molecular Simulations Study. Journal of Biomolecular Structure and Dynamics 2022, 40 (4), 1671–1691. https://doi.org/10.1080/07391102.2020.1831960.. in Journal of Biomolecular Structure and Dynamics. 2022;.
https://hdl.handle.net/21.15107/rcub_cherry_4980 .

Vitorović-Todorović, Maja D., Cvijetić, Ilija, Zloh, Mire, Perdih, Andrej, "Supplementary data for the article: Vitorović-Todorović, M.; Cvijetić, I.; Zloh, M.; Perdih, A. Molecular Recognition of Acetylcholinesterase and Its Subnanomolar Reversible Inhibitor: A Molecular Simulations Study. Journal of Biomolecular Structure and Dynamics 2022, 40 (4), 1671–1691. https://doi.org/10.1080/07391102.2020.1831960." in Journal of Biomolecular Structure and Dynamics (2022),
https://hdl.handle.net/21.15107/rcub_cherry_4980 .

TY  - DATA
AU  - Vitorović-Todorović, Maja D.
AU  - Worek, Franz
AU  - Perdih, Andrej
AU  - Bauk, Sonja Đ.
AU  - Vujatović, Tamara B.
AU  - Cvijetić, Ilija
PY  - 2019
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/3301
PB  - Elsevier
T2  - Chemico-Biological Interactions
T1  - Supplementary material for the article: Vitorović-Todorović, M. D.; Worek, F.; Perdih, A.; Bauk, S. Đ.; Vujatović, T. B.; Cvijetić, I. N. The in Vitro Protective Effects of the Three Novel Nanomolar Reversible Inhibitors of Human Cholinesterases against Irreversible Inhibition by Organophosphorous Chemical Warfare Agents. Chemico-Biological Interactions 2019, 309. https://doi.org/10.1016/j.cbi.2019.06.027
UR  - https://hdl.handle.net/21.15107/rcub_cherry_3301
ER  - 

@misc{
author = "Vitorović-Todorović, Maja D. and Worek, Franz and Perdih, Andrej and Bauk, Sonja Đ. and Vujatović, Tamara B. and Cvijetić, Ilija",
year = "2019",
publisher = "Elsevier",
journal = "Chemico-Biological Interactions",
title = "Supplementary material for the article: Vitorović-Todorović, M. D.; Worek, F.; Perdih, A.; Bauk, S. Đ.; Vujatović, T. B.; Cvijetić, I. N. The in Vitro Protective Effects of the Three Novel Nanomolar Reversible Inhibitors of Human Cholinesterases against Irreversible Inhibition by Organophosphorous Chemical Warfare Agents. Chemico-Biological Interactions 2019, 309. https://doi.org/10.1016/j.cbi.2019.06.027",
url = "https://hdl.handle.net/21.15107/rcub_cherry_3301"
}

Vitorović-Todorović, M. D., Worek, F., Perdih, A., Bauk, S. Đ., Vujatović, T. B.,& Cvijetić, I.. (2019). Supplementary material for the article: Vitorović-Todorović, M. D.; Worek, F.; Perdih, A.; Bauk, S. Đ.; Vujatović, T. B.; Cvijetić, I. N. The in Vitro Protective Effects of the Three Novel Nanomolar Reversible Inhibitors of Human Cholinesterases against Irreversible Inhibition by Organophosphorous Chemical Warfare Agents. Chemico-Biological Interactions 2019, 309. https://doi.org/10.1016/j.cbi.2019.06.027. in Chemico-Biological Interactions
Elsevier..
https://hdl.handle.net/21.15107/rcub_cherry_3301

Vitorović-Todorović MD, Worek F, Perdih A, Bauk SĐ, Vujatović TB, Cvijetić I. Supplementary material for the article: Vitorović-Todorović, M. D.; Worek, F.; Perdih, A.; Bauk, S. Đ.; Vujatović, T. B.; Cvijetić, I. N. The in Vitro Protective Effects of the Three Novel Nanomolar Reversible Inhibitors of Human Cholinesterases against Irreversible Inhibition by Organophosphorous Chemical Warfare Agents. Chemico-Biological Interactions 2019, 309. https://doi.org/10.1016/j.cbi.2019.06.027. in Chemico-Biological Interactions. 2019;.
https://hdl.handle.net/21.15107/rcub_cherry_3301 .

Vitorović-Todorović, Maja D., Worek, Franz, Perdih, Andrej, Bauk, Sonja Đ., Vujatović, Tamara B., Cvijetić, Ilija, "Supplementary material for the article: Vitorović-Todorović, M. D.; Worek, F.; Perdih, A.; Bauk, S. Đ.; Vujatović, T. B.; Cvijetić, I. N. The in Vitro Protective Effects of the Three Novel Nanomolar Reversible Inhibitors of Human Cholinesterases against Irreversible Inhibition by Organophosphorous Chemical Warfare Agents. Chemico-Biological Interactions 2019, 309. https://doi.org/10.1016/j.cbi.2019.06.027" in Chemico-Biological Interactions (2019),
https://hdl.handle.net/21.15107/rcub_cherry_3301 .

TY  - JOUR
AU  - Vitorović-Todorović, Maja D.
AU  - Worek, Franz
AU  - Perdih, Andrej
AU  - Bauk, Sonja Đ.
AU  - Vujatović, Tamara B.
AU  - Cvijetić, Ilija
PY  - 2019
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/3300
AB  - Acetylcholinesterase (AChE) is an enzyme which terminates the cholinergic neurotransmission, by hydrolyzing acetylcholine at the nerve and nerve-muscle junctions. The reversible inhibition of AChE was suggested as the pre-treatment option of the intoxications caused by nerve agents. Based on our derived 3D-QSAR model for the reversible AChE inhibitors, we designed and synthesized three novel compounds 8-10, joining the tacrine and aroylacrylic acid phenylamide moieties, with a longer methylene chain to target two distinct, toplogically separated anionic areas on the AChE. The targeted compounds exerted low nanomolar to subnanomolar potency toward the E. eel and human AChE's as well as the human BChE and showed mixed inhibition type in kinetic studies. All compounds were able to slow down the irreversible inhibition of the human AChE by several nerve agents including tabun, soman and VX, with the estimated protective indices around 5, indicating a valuable level of protection. Putative noncovalent interactions of the selected ligand 10 with AChE active site gorge were finally explored by molecular dynamics simulation suggesting a formation of the salt bridge between the protonated linker amino group and the negatively charged Asp74 carboxylate side chain as a significant player for the successful molecular recognition in line with the design strategy. The designed compounds may represent a new class of promising leads for the development of more effective pre-treatment options.
PB  - Elsevier
T2  - Chemico-Biological Interactions
T1  - The in vitro protective effects of the three novel nanomolar reversible inhibitors of human cholinesterases against irreversible inhibition by organophosphorous chemical warfare agents
VL  - 309
DO  - 10.1016/j.cbi.2019.06.027
ER  - 

@article{
author = "Vitorović-Todorović, Maja D. and Worek, Franz and Perdih, Andrej and Bauk, Sonja Đ. and Vujatović, Tamara B. and Cvijetić, Ilija",
year = "2019",
abstract = "Acetylcholinesterase (AChE) is an enzyme which terminates the cholinergic neurotransmission, by hydrolyzing acetylcholine at the nerve and nerve-muscle junctions. The reversible inhibition of AChE was suggested as the pre-treatment option of the intoxications caused by nerve agents. Based on our derived 3D-QSAR model for the reversible AChE inhibitors, we designed and synthesized three novel compounds 8-10, joining the tacrine and aroylacrylic acid phenylamide moieties, with a longer methylene chain to target two distinct, toplogically separated anionic areas on the AChE. The targeted compounds exerted low nanomolar to subnanomolar potency toward the E. eel and human AChE's as well as the human BChE and showed mixed inhibition type in kinetic studies. All compounds were able to slow down the irreversible inhibition of the human AChE by several nerve agents including tabun, soman and VX, with the estimated protective indices around 5, indicating a valuable level of protection. Putative noncovalent interactions of the selected ligand 10 with AChE active site gorge were finally explored by molecular dynamics simulation suggesting a formation of the salt bridge between the protonated linker amino group and the negatively charged Asp74 carboxylate side chain as a significant player for the successful molecular recognition in line with the design strategy. The designed compounds may represent a new class of promising leads for the development of more effective pre-treatment options.",
publisher = "Elsevier",
journal = "Chemico-Biological Interactions",
title = "The in vitro protective effects of the three novel nanomolar reversible inhibitors of human cholinesterases against irreversible inhibition by organophosphorous chemical warfare agents",
volume = "309",
doi = "10.1016/j.cbi.2019.06.027"
}

Vitorović-Todorović, M. D., Worek, F., Perdih, A., Bauk, S. Đ., Vujatović, T. B.,& Cvijetić, I.. (2019). The in vitro protective effects of the three novel nanomolar reversible inhibitors of human cholinesterases against irreversible inhibition by organophosphorous chemical warfare agents. in Chemico-Biological Interactions
Elsevier., 309.
https://doi.org/10.1016/j.cbi.2019.06.027

Vitorović-Todorović MD, Worek F, Perdih A, Bauk SĐ, Vujatović TB, Cvijetić I. The in vitro protective effects of the three novel nanomolar reversible inhibitors of human cholinesterases against irreversible inhibition by organophosphorous chemical warfare agents. in Chemico-Biological Interactions. 2019;309.
doi:10.1016/j.cbi.2019.06.027 .

Vitorović-Todorović, Maja D., Worek, Franz, Perdih, Andrej, Bauk, Sonja Đ., Vujatović, Tamara B., Cvijetić, Ilija, "The in vitro protective effects of the three novel nanomolar reversible inhibitors of human cholinesterases against irreversible inhibition by organophosphorous chemical warfare agents" in Chemico-Biological Interactions, 309 (2019),
https://doi.org/10.1016/j.cbi.2019.06.027 . .