TY  - JOUR
AU  - Đikić, Teodora
AU  - Vučićević, Jelica
AU  - Laurila, Jonne
AU  - Radi, Marco
AU  - Veljković, Nevena V.
AU  - Xhaard, Henri
AU  - Nikolić, Katarina M.
PY  - 2020
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8887
AB  - Based on the finding that a central antihypertensive agent with high affinity for I1-type imidazoline receptors – rilmenidine, shows cytotoxic effects on cultured cancer cell lines, it has been suggested that imidazoline receptors agonists might have a therapeutic potential in the cancer therapy. Nevertheless, potential rilmenidine side effects caused by activation of α-adrenoceptors, or other associated receptors and enzymes, might hinder its therapeutic benefits. Considering that human α-adrenoceptors belong to the rhodopsin-like class A of G-protein-coupled receptors (GPCRs) it is reasonable to assume that imidazolines might have the affinity for other receptors from the same class. Therefore, to investigate possible off-target effects of imidazoline ligands we have prepared a reverse docking protocol on class A GPCRs, using imidazoline ligands and their decoys. To verify our in silico results, three ligands with high scores and three ligands with low scores were tested for antagonistic activity on α2- adrenoceptors.
T2  - Molecular Informatics
T1  - Deciphering Imidazoline Off‐targets by Fishing in the Class A of GPCR field
VL  - 39
IS  - 7
SP  - 1900165
DO  - 10.1002/minf.201900165
ER  - 

@article{
author = "Đikić, Teodora and Vučićević, Jelica and Laurila, Jonne and Radi, Marco and Veljković, Nevena V. and Xhaard, Henri and Nikolić, Katarina M.",
year = "2020",
abstract = "Based on the finding that a central antihypertensive agent with high affinity for I1-type imidazoline receptors – rilmenidine, shows cytotoxic effects on cultured cancer cell lines, it has been suggested that imidazoline receptors agonists might have a therapeutic potential in the cancer therapy. Nevertheless, potential rilmenidine side effects caused by activation of α-adrenoceptors, or other associated receptors and enzymes, might hinder its therapeutic benefits. Considering that human α-adrenoceptors belong to the rhodopsin-like class A of G-protein-coupled receptors (GPCRs) it is reasonable to assume that imidazolines might have the affinity for other receptors from the same class. Therefore, to investigate possible off-target effects of imidazoline ligands we have prepared a reverse docking protocol on class A GPCRs, using imidazoline ligands and their decoys. To verify our in silico results, three ligands with high scores and three ligands with low scores were tested for antagonistic activity on α2- adrenoceptors.",
journal = "Molecular Informatics",
title = "Deciphering Imidazoline Off‐targets by Fishing in the Class A of GPCR field",
volume = "39",
number = "7",
pages = "1900165",
doi = "10.1002/minf.201900165"
}

Đikić, T., Vučićević, J., Laurila, J., Radi, M., Veljković, N. V., Xhaard, H.,& Nikolić, K. M.. (2020). Deciphering Imidazoline Off‐targets by Fishing in the Class A of GPCR field. in Molecular Informatics, 39(7), 1900165.
https://doi.org/10.1002/minf.201900165

Đikić T, Vučićević J, Laurila J, Radi M, Veljković NV, Xhaard H, Nikolić KM. Deciphering Imidazoline Off‐targets by Fishing in the Class A of GPCR field. in Molecular Informatics. 2020;39(7):1900165.
doi:10.1002/minf.201900165 .

Đikić, Teodora, Vučićević, Jelica, Laurila, Jonne, Radi, Marco, Veljković, Nevena V., Xhaard, Henri, Nikolić, Katarina M., "Deciphering Imidazoline Off‐targets by Fishing in the Class A of GPCR field" in Molecular Informatics, 39, no. 7 (2020):1900165,
https://doi.org/10.1002/minf.201900165 . .

TY  - JOUR
AU  - Vučićević, Jelica
AU  - Srdić-Rajić, Tatjana
AU  - Pieroni, Marco
AU  - Laurila, Jonne M. M.
AU  - Perović, Vladimir R.
AU  - Tassini, Sabrina
AU  - Azzali, Elisa
AU  - Costantino, Gabriele
AU  - Glišić, Sanja
AU  - Agbaba, Danica
AU  - Scheinin, Mika
AU  - Nikolić, Katarina M.
AU  - Radi, Marco
AU  - Veljković, Nevena V.
PY  - 2016
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/1110
AB  - The clonidine-like central antihypertensive agent rilmenidine, which has high affinity for I-1-type imidazoline receptors (I-1-IR) was recently found to have cytotoxic effects on cultured cancer cell lines. However, due to its pharmacological effects resulting also from alpha(2)-adrenoceptor activation, rilmenidine cannot be considered a suitable anticancer drug candidate. Here, we report the identification of novel rilmenidine- derived compounds with anticancer potential and devoid of alpha(2)-adrenoceptor effects by means of ligand-and structure-based drug design approaches. Starting from a large virtual library, eleven compounds were selected, synthesized and submitted to biological evaluation. The most active compound 5 exhibited a cytotoxic profile similar to that of rilmenidine, but without appreciable affinity to alpha(2)-adrenoceptors. In addition, compound 5 significantly enhanced the apoptotic response to doxorubicin, and may thus represent an important tool for the development of better adjuvant chemotherapeutic strategies for doxorubicin-insensitive cancers. (C) 2016 Elsevier Ltd. All rights reserved.
T2  - Bioorganic and Medicinal Chemistry
T1  - A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin
VL  - 24
IS  - 14
SP  - 3174
EP  - 3183
DO  - 10.1016/j.bmc.2016.05.043
ER  - 

@article{
author = "Vučićević, Jelica and Srdić-Rajić, Tatjana and Pieroni, Marco and Laurila, Jonne M. M. and Perović, Vladimir R. and Tassini, Sabrina and Azzali, Elisa and Costantino, Gabriele and Glišić, Sanja and Agbaba, Danica and Scheinin, Mika and Nikolić, Katarina M. and Radi, Marco and Veljković, Nevena V.",
year = "2016",
abstract = "The clonidine-like central antihypertensive agent rilmenidine, which has high affinity for I-1-type imidazoline receptors (I-1-IR) was recently found to have cytotoxic effects on cultured cancer cell lines. However, due to its pharmacological effects resulting also from alpha(2)-adrenoceptor activation, rilmenidine cannot be considered a suitable anticancer drug candidate. Here, we report the identification of novel rilmenidine- derived compounds with anticancer potential and devoid of alpha(2)-adrenoceptor effects by means of ligand-and structure-based drug design approaches. Starting from a large virtual library, eleven compounds were selected, synthesized and submitted to biological evaluation. The most active compound 5 exhibited a cytotoxic profile similar to that of rilmenidine, but without appreciable affinity to alpha(2)-adrenoceptors. In addition, compound 5 significantly enhanced the apoptotic response to doxorubicin, and may thus represent an important tool for the development of better adjuvant chemotherapeutic strategies for doxorubicin-insensitive cancers. (C) 2016 Elsevier Ltd. All rights reserved.",
journal = "Bioorganic and Medicinal Chemistry",
title = "A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin",
volume = "24",
number = "14",
pages = "3174-3183",
doi = "10.1016/j.bmc.2016.05.043"
}

Vučićević, J., Srdić-Rajić, T., Pieroni, M., Laurila, J. M. M., Perović, V. R., Tassini, S., Azzali, E., Costantino, G., Glišić, S., Agbaba, D., Scheinin, M., Nikolić, K. M., Radi, M.,& Veljković, N. V.. (2016). A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin. in Bioorganic and Medicinal Chemistry, 24(14), 3174-3183.
https://doi.org/10.1016/j.bmc.2016.05.043

Vučićević J, Srdić-Rajić T, Pieroni M, Laurila JMM, Perović VR, Tassini S, Azzali E, Costantino G, Glišić S, Agbaba D, Scheinin M, Nikolić KM, Radi M, Veljković NV. A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin. in Bioorganic and Medicinal Chemistry. 2016;24(14):3174-3183.
doi:10.1016/j.bmc.2016.05.043 .

Vučićević, Jelica, Srdić-Rajić, Tatjana, Pieroni, Marco, Laurila, Jonne M. M., Perović, Vladimir R., Tassini, Sabrina, Azzali, Elisa, Costantino, Gabriele, Glišić, Sanja, Agbaba, Danica, Scheinin, Mika, Nikolić, Katarina M., Radi, Marco, Veljković, Nevena V., "A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin" in Bioorganic and Medicinal Chemistry, 24, no. 14 (2016):3174-3183,
https://doi.org/10.1016/j.bmc.2016.05.043 . .

TY  - JOUR
AU  - Veljković, Nevena V.
AU  - Vučićević, Jelica
AU  - Tassini, Sabrina
AU  - Glišić, Sanja
AU  - Veljković, Veljko
AU  - Radi, Marco
PY  - 2015
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/558
AB  - Introduction: Maraviroc is a first-in-class antiretroviral (ARV) drug acting on a host cell target (CCR5), which blocks the entry of the HIV virus into the cell. Maraviroc is currently indicated for combination ARV treatment in adults infected only with CCR5-tropic HIV-1. Areas covered: This drug discovery case history focuses on the key studies that led to the discovery and approval of maraviroc, as well as on post-launch clinical reports. The article is based on the data reported in published preclinical and clinical studies, conference posters and on drug package data. Expert opinion: The profound understanding of HIVs entry mechanisms has provided a strong biological rationale for targeting the chemokine receptor CCR5. The CCR5-antagonist mariviroc, with its unique mode of action and excellent safety profile, is an important therapeutic option for HIV patients. In general, the authors believe that targeting host factors is a useful approach for combating new and re-emerging transmissible diseases, as well as pathogens that easily become resistant to common antiviral drugs. Maraviroc, offering a potent and safe cellular receptor-mediated pharmacological response to HIV, has paved the way for the development of a new generation of host-targeting antivirals.
T2  - Expert Opinion on Drug Discovery
T1  - Preclinical discovery and development of maraviroc for the treatment of HIV
VL  - 10
IS  - 6
SP  - 671
EP  - 684
DO  - 10.1517/17460441.2015.1041497
ER  - 

@article{
author = "Veljković, Nevena V. and Vučićević, Jelica and Tassini, Sabrina and Glišić, Sanja and Veljković, Veljko and Radi, Marco",
year = "2015",
abstract = "Introduction: Maraviroc is a first-in-class antiretroviral (ARV) drug acting on a host cell target (CCR5), which blocks the entry of the HIV virus into the cell. Maraviroc is currently indicated for combination ARV treatment in adults infected only with CCR5-tropic HIV-1. Areas covered: This drug discovery case history focuses on the key studies that led to the discovery and approval of maraviroc, as well as on post-launch clinical reports. The article is based on the data reported in published preclinical and clinical studies, conference posters and on drug package data. Expert opinion: The profound understanding of HIVs entry mechanisms has provided a strong biological rationale for targeting the chemokine receptor CCR5. The CCR5-antagonist mariviroc, with its unique mode of action and excellent safety profile, is an important therapeutic option for HIV patients. In general, the authors believe that targeting host factors is a useful approach for combating new and re-emerging transmissible diseases, as well as pathogens that easily become resistant to common antiviral drugs. Maraviroc, offering a potent and safe cellular receptor-mediated pharmacological response to HIV, has paved the way for the development of a new generation of host-targeting antivirals.",
journal = "Expert Opinion on Drug Discovery",
title = "Preclinical discovery and development of maraviroc for the treatment of HIV",
volume = "10",
number = "6",
pages = "671-684",
doi = "10.1517/17460441.2015.1041497"
}

Veljković, N. V., Vučićević, J., Tassini, S., Glišić, S., Veljković, V.,& Radi, M.. (2015). Preclinical discovery and development of maraviroc for the treatment of HIV. in Expert Opinion on Drug Discovery, 10(6), 671-684.
https://doi.org/10.1517/17460441.2015.1041497

Veljković NV, Vučićević J, Tassini S, Glišić S, Veljković V, Radi M. Preclinical discovery and development of maraviroc for the treatment of HIV. in Expert Opinion on Drug Discovery. 2015;10(6):671-684.
doi:10.1517/17460441.2015.1041497 .

Veljković, Nevena V., Vučićević, Jelica, Tassini, Sabrina, Glišić, Sanja, Veljković, Veljko, Radi, Marco, "Preclinical discovery and development of maraviroc for the treatment of HIV" in Expert Opinion on Drug Discovery, 10, no. 6 (2015):671-684,
https://doi.org/10.1517/17460441.2015.1041497 . .

TY  - JOUR
AU  - Nikolić, Katarina M.
AU  - Veljković, Nevena V.
AU  - Gemović, Branislava S.
AU  - Srdić-Rajić, Tatjana
AU  - Agbaba, Danica
PY  - 2013
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/5398
AB  - The group of imidazoline-1 receptors (I-1-IR) agonists encompasses drugs are currently used in treatment of high blood pressure and hyperglycemia. The I-1-IR protein structures have not been determined yet, but Nischarin protein that binds numerous imidazoline ligands inducing initiation of various cell-signaling cascades, including apoptosis, is identified as strong I-1-IR candidate. In this study we examined apoptotic activity of rilmenidine (potent I-1-IR agonist), moxonidine (moderate I-1-IR agonist), and efaroxan (I-1-IR partial agonist) on cancer cell line (K562) expressing Nischarin. The Nischarine domains mapping was performed by use of the Informational Spectrum Method (ISM). The 3D-Quantitative Structure-Activity Relationship (3D-QSAR) and virtual docking studies of 29 I-1-IR ligands (agonists, partial agonists, and antagonists) were carried out on I-1-IR receptors binding affinities. The 3D-QSAR study defined 3D-pharmacophore models for I-1-IR agonistic and I-1-IR antagonistic activity and created regression model for prediction of I-1-IR activity of novel compounds. The 3D-QSAR models were applied for design and evaluation of novel I-1-IR agonists and I-1-IR antagonists. The most promising I-1-IR ligands with enhanced activities than parent compounds were proposed for synthesis. The results of 3D-QSAR, ISM, and virtual docking studies were in perfect agreement and allowed precise definition of binding mode of I-1-IR agonists (Arg 758, Arg 866, Val 981, and Glu 1057) and significantly different binding modes of I-1-IR antagonists or partial I-1-IR agonists. The performed theoretical study provides reliable system for evaluation of I-1-IR agonistic and I-1-IR antagonistic activity of novel I-1-IR ligands, as drug candidates with anticancer activities.
T2  - Combinatorial Chemistry and High Throughput Screening
T1  - Imidazoline-1 Receptor Ligands as Apoptotic Agents: Pharmacophore Modeling and Virtual Docking Study
VL  - 16
IS  - 4
SP  - 298
EP  - 319
DO  - 10.2174/1386207311316040004
ER  - 

@article{
author = "Nikolić, Katarina M. and Veljković, Nevena V. and Gemović, Branislava S. and Srdić-Rajić, Tatjana and Agbaba, Danica",
year = "2013",
abstract = "The group of imidazoline-1 receptors (I-1-IR) agonists encompasses drugs are currently used in treatment of high blood pressure and hyperglycemia. The I-1-IR protein structures have not been determined yet, but Nischarin protein that binds numerous imidazoline ligands inducing initiation of various cell-signaling cascades, including apoptosis, is identified as strong I-1-IR candidate. In this study we examined apoptotic activity of rilmenidine (potent I-1-IR agonist), moxonidine (moderate I-1-IR agonist), and efaroxan (I-1-IR partial agonist) on cancer cell line (K562) expressing Nischarin. The Nischarine domains mapping was performed by use of the Informational Spectrum Method (ISM). The 3D-Quantitative Structure-Activity Relationship (3D-QSAR) and virtual docking studies of 29 I-1-IR ligands (agonists, partial agonists, and antagonists) were carried out on I-1-IR receptors binding affinities. The 3D-QSAR study defined 3D-pharmacophore models for I-1-IR agonistic and I-1-IR antagonistic activity and created regression model for prediction of I-1-IR activity of novel compounds. The 3D-QSAR models were applied for design and evaluation of novel I-1-IR agonists and I-1-IR antagonists. The most promising I-1-IR ligands with enhanced activities than parent compounds were proposed for synthesis. The results of 3D-QSAR, ISM, and virtual docking studies were in perfect agreement and allowed precise definition of binding mode of I-1-IR agonists (Arg 758, Arg 866, Val 981, and Glu 1057) and significantly different binding modes of I-1-IR antagonists or partial I-1-IR agonists. The performed theoretical study provides reliable system for evaluation of I-1-IR agonistic and I-1-IR antagonistic activity of novel I-1-IR ligands, as drug candidates with anticancer activities.",
journal = "Combinatorial Chemistry and High Throughput Screening",
title = "Imidazoline-1 Receptor Ligands as Apoptotic Agents: Pharmacophore Modeling and Virtual Docking Study",
volume = "16",
number = "4",
pages = "298-319",
doi = "10.2174/1386207311316040004"
}

Nikolić, K. M., Veljković, N. V., Gemović, B. S., Srdić-Rajić, T.,& Agbaba, D.. (2013). Imidazoline-1 Receptor Ligands as Apoptotic Agents: Pharmacophore Modeling and Virtual Docking Study. in Combinatorial Chemistry and High Throughput Screening, 16(4), 298-319.
https://doi.org/10.2174/1386207311316040004

Nikolić KM, Veljković NV, Gemović BS, Srdić-Rajić T, Agbaba D. Imidazoline-1 Receptor Ligands as Apoptotic Agents: Pharmacophore Modeling and Virtual Docking Study. in Combinatorial Chemistry and High Throughput Screening. 2013;16(4):298-319.
doi:10.2174/1386207311316040004 .

Nikolić, Katarina M., Veljković, Nevena V., Gemović, Branislava S., Srdić-Rajić, Tatjana, Agbaba, Danica, "Imidazoline-1 Receptor Ligands as Apoptotic Agents: Pharmacophore Modeling and Virtual Docking Study" in Combinatorial Chemistry and High Throughput Screening, 16, no. 4 (2013):298-319,
https://doi.org/10.2174/1386207311316040004 . .