Design of Dual COX-2 and 5-LOX Inhibitors with Iron-Chelating Properties Using Structure-Based and Ligand-Based Methods
Само за регистроване кориснике
2022
Чланак у часопису (Објављена верзија)
Метаподаци
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Background: Inflammation is a critical component of many disease progressions, such as malignancy, cardiovascular and rheumatic diseases. The inhibition of inflammatory mediators synthesis by modulation of cyclooxygenase (COX) and lipoxygenase (LOX) pathways provides challenging strategy for development of more effective drugs.
Objective: The aim of this study was to design dual COX-2 and 5-LOX inhibitors with iron-chelating properties using a combination of ligand-based (three-dimensional quantitative structure-activity relationship (3D-QSAR)) and structure-based (molecular docking) methods..
Methods: The 3D-QSAR analysis was applied on a literature dataset consisting of 28 dual COX-2 and 5- LOX inhibitors in Pentacle software. The quality of developed COX-2 and 5-LOX 3D-QSAR models were evaluated by internal and external validation methods. The molecular docking analysis was performed in GOLD software, while selected ADMET properties were predicted in ADMET predictor software.
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Results: According to the molecular docking studies, the class of sulfohydroxamic acid analogues, previously designed by 3D-QSAR, were clustered as potential dual COX-2 and 5-LOX inhibitors with ironchelating properties. Based on the 3D-QSAR and molecular docking, 1j, 1g and 1l were selected as the most promising dual COX-2 and 5-LOX inhibitors. According to the in silico ADMET predictions, all compounds had ADMET_Risk score less than 7 and CYP_Risk score lower than 2.5. Designed compounds were not estimated as hERG inhibitors and 1j had improved intrinsic solubility (8.704) in comparison to the dataset compounds (0.411-7.946).
Conclusion: By combining 3D-QSAR and molecular docking, three compounds (1j, 1g and 1l) were selected as the most promising designed dual COX-2 and 5-LOX inhibitors, for which good activity, as well as favourable ADMET properties and toxicity, are expected.
Кључне речи:
Drug design / 3D-QSAR / molecular docking / iron chelation / dual COX-2 and 5-LOX inhibitors / ADMET predictionИзвор:
Letters in Drug Design & Discovery, 2022, 19, 4, 279-292Издавач:
- Bentham Science Publishers
Финансирање / пројекти:
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200161 (Универзитет у Београду, Фармацеутски факултет) (RS-MESTD-inst-2020-200161)
DOI: 10.2174/1570180818666210714161908
ISSN: 1570-1808
WoS: 000819387600003
Scopus: 2-s2.0-85129709248
Институција/група
PharmacyTY - JOUR AU - Bošković, Jelena AU - Ružić, Dušan AU - Čudina, Olivera AU - Nikolić, Katarina AU - Dobričić, Vladimir PY - 2022 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5442 AB - Background: Inflammation is a critical component of many disease progressions, such as malignancy, cardiovascular and rheumatic diseases. The inhibition of inflammatory mediators synthesis by modulation of cyclooxygenase (COX) and lipoxygenase (LOX) pathways provides challenging strategy for development of more effective drugs. Objective: The aim of this study was to design dual COX-2 and 5-LOX inhibitors with iron-chelating properties using a combination of ligand-based (three-dimensional quantitative structure-activity relationship (3D-QSAR)) and structure-based (molecular docking) methods.. Methods: The 3D-QSAR analysis was applied on a literature dataset consisting of 28 dual COX-2 and 5- LOX inhibitors in Pentacle software. The quality of developed COX-2 and 5-LOX 3D-QSAR models were evaluated by internal and external validation methods. The molecular docking analysis was performed in GOLD software, while selected ADMET properties were predicted in ADMET predictor software. Results: According to the molecular docking studies, the class of sulfohydroxamic acid analogues, previously designed by 3D-QSAR, were clustered as potential dual COX-2 and 5-LOX inhibitors with ironchelating properties. Based on the 3D-QSAR and molecular docking, 1j, 1g and 1l were selected as the most promising dual COX-2 and 5-LOX inhibitors. According to the in silico ADMET predictions, all compounds had ADMET_Risk score less than 7 and CYP_Risk score lower than 2.5. Designed compounds were not estimated as hERG inhibitors and 1j had improved intrinsic solubility (8.704) in comparison to the dataset compounds (0.411-7.946). Conclusion: By combining 3D-QSAR and molecular docking, three compounds (1j, 1g and 1l) were selected as the most promising designed dual COX-2 and 5-LOX inhibitors, for which good activity, as well as favourable ADMET properties and toxicity, are expected. PB - Bentham Science Publishers T2 - Letters in Drug Design & Discovery T1 - Design of Dual COX-2 and 5-LOX Inhibitors with Iron-Chelating Properties Using Structure-Based and Ligand-Based Methods VL - 19 IS - 4 SP - 279 EP - 292 DO - 10.2174/1570180818666210714161908 ER -
@article{ author = "Bošković, Jelena and Ružić, Dušan and Čudina, Olivera and Nikolić, Katarina and Dobričić, Vladimir", year = "2022", abstract = "Background: Inflammation is a critical component of many disease progressions, such as malignancy, cardiovascular and rheumatic diseases. The inhibition of inflammatory mediators synthesis by modulation of cyclooxygenase (COX) and lipoxygenase (LOX) pathways provides challenging strategy for development of more effective drugs. Objective: The aim of this study was to design dual COX-2 and 5-LOX inhibitors with iron-chelating properties using a combination of ligand-based (three-dimensional quantitative structure-activity relationship (3D-QSAR)) and structure-based (molecular docking) methods.. Methods: The 3D-QSAR analysis was applied on a literature dataset consisting of 28 dual COX-2 and 5- LOX inhibitors in Pentacle software. The quality of developed COX-2 and 5-LOX 3D-QSAR models were evaluated by internal and external validation methods. The molecular docking analysis was performed in GOLD software, while selected ADMET properties were predicted in ADMET predictor software. Results: According to the molecular docking studies, the class of sulfohydroxamic acid analogues, previously designed by 3D-QSAR, were clustered as potential dual COX-2 and 5-LOX inhibitors with ironchelating properties. Based on the 3D-QSAR and molecular docking, 1j, 1g and 1l were selected as the most promising dual COX-2 and 5-LOX inhibitors. According to the in silico ADMET predictions, all compounds had ADMET_Risk score less than 7 and CYP_Risk score lower than 2.5. Designed compounds were not estimated as hERG inhibitors and 1j had improved intrinsic solubility (8.704) in comparison to the dataset compounds (0.411-7.946). Conclusion: By combining 3D-QSAR and molecular docking, three compounds (1j, 1g and 1l) were selected as the most promising designed dual COX-2 and 5-LOX inhibitors, for which good activity, as well as favourable ADMET properties and toxicity, are expected.", publisher = "Bentham Science Publishers", journal = "Letters in Drug Design & Discovery", title = "Design of Dual COX-2 and 5-LOX Inhibitors with Iron-Chelating Properties Using Structure-Based and Ligand-Based Methods", volume = "19", number = "4", pages = "279-292", doi = "10.2174/1570180818666210714161908" }
Bošković, J., Ružić, D., Čudina, O., Nikolić, K.,& Dobričić, V.. (2022). Design of Dual COX-2 and 5-LOX Inhibitors with Iron-Chelating Properties Using Structure-Based and Ligand-Based Methods. in Letters in Drug Design & Discovery Bentham Science Publishers., 19(4), 279-292. https://doi.org/10.2174/1570180818666210714161908
Bošković J, Ružić D, Čudina O, Nikolić K, Dobričić V. Design of Dual COX-2 and 5-LOX Inhibitors with Iron-Chelating Properties Using Structure-Based and Ligand-Based Methods. in Letters in Drug Design & Discovery. 2022;19(4):279-292. doi:10.2174/1570180818666210714161908 .
Bošković, Jelena, Ružić, Dušan, Čudina, Olivera, Nikolić, Katarina, Dobričić, Vladimir, "Design of Dual COX-2 and 5-LOX Inhibitors with Iron-Chelating Properties Using Structure-Based and Ligand-Based Methods" in Letters in Drug Design & Discovery, 19, no. 4 (2022):279-292, https://doi.org/10.2174/1570180818666210714161908 . .