Design of novel dual COX 2 and 5 LOX inhibitors using quantitative structure activity relationships analysis
Апстракт
Inflammation is a part of immune system's response to harmful intrinsic and
extrinsic stimuli, such as infection or injury. It has an important role in progression of some diseases, such as cancer, arthritis, stroke [1]. It is considered that inhibition of COX 2 and 5 LOX pathways of production of inflammation mediators provides a new strategy for development of more effective anticancer drugs [2]. The aim of this study was designing of novel COX 2/5 LOX inhibitors with improved activity towards both enzymes using quantitative structure activity relationships (QSAR). QSAR modeling was applied on a literature data set consisting of 28 dual COX 2/5 LOX inhibitors and obtained pharmacophoric features were used in design of novel compounds. Regarding prediction of activity of novel COX 2 and 5 LOX inhibitors, two models were developed. Based on values of Q2 (0.53 (COX 2 model) and 0.71 (5 LOX model)) and R2 pred (0.85 (for both COX 2 and 5 LOX models)), developed models have good predicti...ve ability and can be used for activity prediction of novel designed compounds.
Obtained values of r2m, r'2m, and r ̅2m were higher than 0.5 and Δr2m was lower than 0.2 indicating high predictive quality of developed models. Applicability domain (AD) was defined using Leverage approach and all compounds were inside the AD. In order to get more potent dual inhibitors of COX 2 and 5 LOX enzymes, compounds with high pIC50 values were chosen for design of novel compounds. As a result, 32 novel compounds were designed and according to predicted pIC50 values can be considered promising dual COX 2 and 5 LOX inhibitors.
Извор:
MedChem 2022, XI Paul Ehrlich Euro-PhD Network, Barcelona, July 14th - 16th 2022, Book of Abstracts, 2022, 57-57Издавач:
- Institut Químic de Sarrià - Universitat Ramon Llull (IQS-URL)
Институција/група
PharmacyTY - CONF AU - Bošković, Jelena AU - Dobričić, Vladimir AU - Ružić, Dušan AU - Nikolić, Katarina AU - Čudina, Olivera PY - 2022 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5451 AB - Inflammation is a part of immune system's response to harmful intrinsic and extrinsic stimuli, such as infection or injury. It has an important role in progression of some diseases, such as cancer, arthritis, stroke [1]. It is considered that inhibition of COX 2 and 5 LOX pathways of production of inflammation mediators provides a new strategy for development of more effective anticancer drugs [2]. The aim of this study was designing of novel COX 2/5 LOX inhibitors with improved activity towards both enzymes using quantitative structure activity relationships (QSAR). QSAR modeling was applied on a literature data set consisting of 28 dual COX 2/5 LOX inhibitors and obtained pharmacophoric features were used in design of novel compounds. Regarding prediction of activity of novel COX 2 and 5 LOX inhibitors, two models were developed. Based on values of Q2 (0.53 (COX 2 model) and 0.71 (5 LOX model)) and R2 pred (0.85 (for both COX 2 and 5 LOX models)), developed models have good predictive ability and can be used for activity prediction of novel designed compounds. Obtained values of r2m, r'2m, and r ̅2m were higher than 0.5 and Δr2m was lower than 0.2 indicating high predictive quality of developed models. Applicability domain (AD) was defined using Leverage approach and all compounds were inside the AD. In order to get more potent dual inhibitors of COX 2 and 5 LOX enzymes, compounds with high pIC50 values were chosen for design of novel compounds. As a result, 32 novel compounds were designed and according to predicted pIC50 values can be considered promising dual COX 2 and 5 LOX inhibitors. PB - Institut Químic de Sarrià - Universitat Ramon Llull (IQS-URL) C3 - MedChem 2022, XI Paul Ehrlich Euro-PhD Network, Barcelona, July 14th - 16th 2022, Book of Abstracts T1 - Design of novel dual COX 2 and 5 LOX inhibitors using quantitative structure activity relationships analysis SP - 57 EP - 57 UR - https://hdl.handle.net/21.15107/rcub_farfar_5451 ER -
@conference{ author = "Bošković, Jelena and Dobričić, Vladimir and Ružić, Dušan and Nikolić, Katarina and Čudina, Olivera", year = "2022", abstract = "Inflammation is a part of immune system's response to harmful intrinsic and extrinsic stimuli, such as infection or injury. It has an important role in progression of some diseases, such as cancer, arthritis, stroke [1]. It is considered that inhibition of COX 2 and 5 LOX pathways of production of inflammation mediators provides a new strategy for development of more effective anticancer drugs [2]. The aim of this study was designing of novel COX 2/5 LOX inhibitors with improved activity towards both enzymes using quantitative structure activity relationships (QSAR). QSAR modeling was applied on a literature data set consisting of 28 dual COX 2/5 LOX inhibitors and obtained pharmacophoric features were used in design of novel compounds. Regarding prediction of activity of novel COX 2 and 5 LOX inhibitors, two models were developed. Based on values of Q2 (0.53 (COX 2 model) and 0.71 (5 LOX model)) and R2 pred (0.85 (for both COX 2 and 5 LOX models)), developed models have good predictive ability and can be used for activity prediction of novel designed compounds. Obtained values of r2m, r'2m, and r ̅2m were higher than 0.5 and Δr2m was lower than 0.2 indicating high predictive quality of developed models. Applicability domain (AD) was defined using Leverage approach and all compounds were inside the AD. In order to get more potent dual inhibitors of COX 2 and 5 LOX enzymes, compounds with high pIC50 values were chosen for design of novel compounds. As a result, 32 novel compounds were designed and according to predicted pIC50 values can be considered promising dual COX 2 and 5 LOX inhibitors.", publisher = "Institut Químic de Sarrià - Universitat Ramon Llull (IQS-URL)", journal = "MedChem 2022, XI Paul Ehrlich Euro-PhD Network, Barcelona, July 14th - 16th 2022, Book of Abstracts", title = "Design of novel dual COX 2 and 5 LOX inhibitors using quantitative structure activity relationships analysis", pages = "57-57", url = "https://hdl.handle.net/21.15107/rcub_farfar_5451" }
Bošković, J., Dobričić, V., Ružić, D., Nikolić, K.,& Čudina, O.. (2022). Design of novel dual COX 2 and 5 LOX inhibitors using quantitative structure activity relationships analysis. in MedChem 2022, XI Paul Ehrlich Euro-PhD Network, Barcelona, July 14th - 16th 2022, Book of Abstracts Institut Químic de Sarrià - Universitat Ramon Llull (IQS-URL)., 57-57. https://hdl.handle.net/21.15107/rcub_farfar_5451
Bošković J, Dobričić V, Ružić D, Nikolić K, Čudina O. Design of novel dual COX 2 and 5 LOX inhibitors using quantitative structure activity relationships analysis. in MedChem 2022, XI Paul Ehrlich Euro-PhD Network, Barcelona, July 14th - 16th 2022, Book of Abstracts. 2022;:57-57. https://hdl.handle.net/21.15107/rcub_farfar_5451 .
Bošković, Jelena, Dobričić, Vladimir, Ružić, Dušan, Nikolić, Katarina, Čudina, Olivera, "Design of novel dual COX 2 and 5 LOX inhibitors using quantitative structure activity relationships analysis" in MedChem 2022, XI Paul Ehrlich Euro-PhD Network, Barcelona, July 14th - 16th 2022, Book of Abstracts (2022):57-57, https://hdl.handle.net/21.15107/rcub_farfar_5451 .