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Imidazoline-1 Receptor Ligands as Apoptotic Agents: Pharmacophore Modeling and Virtual Docking Study

Authorized Users Only
2013
Authors
Nikolić, Katarina
Veljković, Nevena
Gemović, Branislava
Srdić-Rajić, Tatjana
Agbaba, Danica
Article (Published version)
Metadata
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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 antagonist...ic 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.

Keywords:
Apoptotic activity / I-1-imidazoline receptor / I-1-IR agonist / I-1-IR antagonist / pharmacophore modeling / structure activity relationship / virtual docking
Source:
Combinatorial Chemistry & High Throughput Screening, 2013, 16, 4, 298-319
Publisher:
  • Bentham Science Publ Ltd, Sharjah
Funding / projects:
  • Synthesis, Quantitative Structure and Activity Relationship, Physico-Chemical Characterisation and Analysis of Pharmacologically Active Substances (RS-172033)

DOI: 10.2174/1386207311316040004

ISSN: 1386-2073

PubMed: 23360165

WoS: 000317058100004

Scopus: 2-s2.0-84877962730
[ Google Scholar ]
8
8
URI
https://farfar.pharmacy.bg.ac.rs/handle/123456789/1933
Collections
  • Radovi istraživača / Researchers’ publications
Institution/Community
Pharmacy
TY  - JOUR
AU  - Nikolić, Katarina
AU  - Veljković, Nevena
AU  - Gemović, Branislava
AU  - Srdić-Rajić, Tatjana
AU  - Agbaba, Danica
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1933
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.
PB  - Bentham Science Publ Ltd, Sharjah
T2  - Combinatorial Chemistry & 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
UR  - conv_2813
ER  - 
@article{
author = "Nikolić, Katarina and Veljković, Nevena and Gemović, Branislava 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.",
publisher = "Bentham Science Publ Ltd, Sharjah",
journal = "Combinatorial Chemistry & 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",
url = "conv_2813"
}
Nikolić, K., Veljković, N., Gemović, B., Srdić-Rajić, T.,& Agbaba, D.. (2013). Imidazoline-1 Receptor Ligands as Apoptotic Agents: Pharmacophore Modeling and Virtual Docking Study. in Combinatorial Chemistry & High Throughput Screening
Bentham Science Publ Ltd, Sharjah., 16(4), 298-319.
https://doi.org/10.2174/1386207311316040004
conv_2813
Nikolić K, Veljković N, Gemović B, Srdić-Rajić T, Agbaba D. Imidazoline-1 Receptor Ligands as Apoptotic Agents: Pharmacophore Modeling and Virtual Docking Study. in Combinatorial Chemistry & High Throughput Screening. 2013;16(4):298-319.
doi:10.2174/1386207311316040004
conv_2813 .
Nikolić, Katarina, Veljković, Nevena, Gemović, Branislava, Srdić-Rajić, Tatjana, Agbaba, Danica, "Imidazoline-1 Receptor Ligands as Apoptotic Agents: Pharmacophore Modeling and Virtual Docking Study" in Combinatorial Chemistry & High Throughput Screening, 16, no. 4 (2013):298-319,
https://doi.org/10.2174/1386207311316040004 .,
conv_2813 .

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