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

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2013
Authors
Nikolić, Katarina
Veljković, Nevena
Gemović, Branislava
Srdić-Rajić, Tatjana
Agbaba, Danica
Article (Published version)
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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
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
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URI
http://farfar.pharmacy.bg.ac.rs/handle/123456789/1933
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  • Radovi istraživača / Researchers’ publications
Institution
Pharmacy

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