Imidazoline-1 Receptor Ligands as Apoptotic Agents: Pharmacophore Modeling and Virtual Docking Study
Само за регистроване кориснике
2013
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
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.
Кључне речи:
Apoptotic activity / I-1-imidazoline receptor / I-1-IR agonist / I-1-IR antagonist / pharmacophore modeling / structure activity relationship / virtual dockingИзвор:
Combinatorial Chemistry & High Throughput Screening, 2013, 16, 4, 298-319Издавач:
- Bentham Science Publ Ltd, Sharjah
Финансирање / пројекти:
- Синтеза, квантитативни однос између структуре и дејства, физичко-хемијска карактеризација и анализа фармаколошки активних супстанци (RS-MESTD-Basic Research (BR or ON)-172033)
DOI: 10.2174/1386207311316040004
ISSN: 1386-2073
PubMed: 23360165
WoS: 000317058100004
Scopus: 2-s2.0-84877962730
Институција/група
PharmacyTY - 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 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" }
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
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 .
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 . .