Revealing innovative JAK1 and JAK3 inhibitors: a comprehensive study utilizing QSAR, 3D-Pharmacophore screening, molecular docking, molecular dynamics, and MM/GBSA analyses
The heterocycle compounds, with their diverse functionalities, are particularly effective in inhibiting Janus kinases (JAKs). Therefore, it is crucial to identify the correlation between their complex structures and biological activities for the development of new drugs for the treatment of rheumato...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-03-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2024.1348277/full |
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| author | Abdelmoujoud Faris Ivana Cacciatore Radwan Alnajjar Hadni Hanine Adnane Aouidate Ramzi A. Mothana Abdullah R. Alanzi Menana Elhallaoui |
| author_facet | Abdelmoujoud Faris Ivana Cacciatore Radwan Alnajjar Hadni Hanine Adnane Aouidate Ramzi A. Mothana Abdullah R. Alanzi Menana Elhallaoui |
| author_sort | Abdelmoujoud Faris |
| collection | DOAJ |
| description | The heterocycle compounds, with their diverse functionalities, are particularly effective in inhibiting Janus kinases (JAKs). Therefore, it is crucial to identify the correlation between their complex structures and biological activities for the development of new drugs for the treatment of rheumatoid arthritis (RA) and cancer. In this study, a diverse set of 28 heterocyclic compounds selective for JAK1 and JAK3 was employed to construct quantitative structure-activity relationship (QSAR) models using multiple linear regression (MLR). Artificial neural network (ANN) models were employed in the development of QSAR models. The robustness and stability of the models were assessed through internal and external methodologies, including the domain of applicability (DoA). The molecular descriptors incorporated into the model exhibited a satisfactory correlation with the receptor-ligand complex structures of JAKs observed in X-ray crystallography, making the model interpretable and predictive. Furthermore, pharmacophore models ADRRR and ADHRR were designed for each JAK1 and JAK3, proving effective in discriminating between active compounds and decoys. Both models demonstrated good performance in identifying new compounds, with an ROC of 0.83 for the ADRRR model and an ROC of 0.75 for the ADHRR model. Using a pharmacophore model, the most promising compounds were selected based on their strong affinity compared to the most active compounds in the studied series each JAK1 and JAK3. Notably, the pharmacokinetic, physicochemical properties, and biological activities of the selected compounds (As compounds ZINC79189223 and ZINC66252348) were found to be consistent with their therapeutic effects in RA, owing to their non-toxic, cholinergic nature, absence of P-glycoprotein, high gastrointestinal absorption, and ability to penetrate the blood-brain barrier. Furthermore, ADMET properties were assessed, and molecular dynamics and MM/GBSA analysis revealed stability in these molecules. |
| first_indexed | 2024-04-25T02:09:52Z |
| format | Article |
| id | doaj.art-a92838db09a44b7b80f83538be346eba |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-04-25T02:09:52Z |
| publishDate | 2024-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-a92838db09a44b7b80f83538be346eba2024-03-07T12:57:27ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2024-03-011110.3389/fmolb.2024.13482771348277Revealing innovative JAK1 and JAK3 inhibitors: a comprehensive study utilizing QSAR, 3D-Pharmacophore screening, molecular docking, molecular dynamics, and MM/GBSA analysesAbdelmoujoud Faris0Ivana Cacciatore1Radwan Alnajjar2Hadni Hanine3Adnane Aouidate4Ramzi A. Mothana5Abdullah R. Alanzi6Menana Elhallaoui7LIMAS, Department of Chemical Sciences, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, Fez, MoroccoDepartment of Pharmacy, University ‘G. d’Annunzio’ of Chieti-Pescara, Chieti, ItalyCADD Unit, PharmD, Faculty of Pharmacy, Libyan International Medical University, Benghazi, LibyaLIMAS, Department of Chemical Sciences, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, Fez, MoroccoSchool of Applied Sciences of Ait Melloul, Ibn Zohr University, Fez, MoroccoDepartment of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi ArabiaDepartment of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi ArabiaLIMAS, Department of Chemical Sciences, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, Fez, MoroccoThe heterocycle compounds, with their diverse functionalities, are particularly effective in inhibiting Janus kinases (JAKs). Therefore, it is crucial to identify the correlation between their complex structures and biological activities for the development of new drugs for the treatment of rheumatoid arthritis (RA) and cancer. In this study, a diverse set of 28 heterocyclic compounds selective for JAK1 and JAK3 was employed to construct quantitative structure-activity relationship (QSAR) models using multiple linear regression (MLR). Artificial neural network (ANN) models were employed in the development of QSAR models. The robustness and stability of the models were assessed through internal and external methodologies, including the domain of applicability (DoA). The molecular descriptors incorporated into the model exhibited a satisfactory correlation with the receptor-ligand complex structures of JAKs observed in X-ray crystallography, making the model interpretable and predictive. Furthermore, pharmacophore models ADRRR and ADHRR were designed for each JAK1 and JAK3, proving effective in discriminating between active compounds and decoys. Both models demonstrated good performance in identifying new compounds, with an ROC of 0.83 for the ADRRR model and an ROC of 0.75 for the ADHRR model. Using a pharmacophore model, the most promising compounds were selected based on their strong affinity compared to the most active compounds in the studied series each JAK1 and JAK3. Notably, the pharmacokinetic, physicochemical properties, and biological activities of the selected compounds (As compounds ZINC79189223 and ZINC66252348) were found to be consistent with their therapeutic effects in RA, owing to their non-toxic, cholinergic nature, absence of P-glycoprotein, high gastrointestinal absorption, and ability to penetrate the blood-brain barrier. Furthermore, ADMET properties were assessed, and molecular dynamics and MM/GBSA analysis revealed stability in these molecules.https://www.frontiersin.org/articles/10.3389/fmolb.2024.1348277/fullJanus kinasesFDA-drugcytochrome P450rheumatoid arthritisimmune systeminterleukin |
| spellingShingle | Abdelmoujoud Faris Ivana Cacciatore Radwan Alnajjar Hadni Hanine Adnane Aouidate Ramzi A. Mothana Abdullah R. Alanzi Menana Elhallaoui Revealing innovative JAK1 and JAK3 inhibitors: a comprehensive study utilizing QSAR, 3D-Pharmacophore screening, molecular docking, molecular dynamics, and MM/GBSA analyses Frontiers in Molecular Biosciences Janus kinases FDA-drug cytochrome P450 rheumatoid arthritis immune system interleukin |
| title | Revealing innovative JAK1 and JAK3 inhibitors: a comprehensive study utilizing QSAR, 3D-Pharmacophore screening, molecular docking, molecular dynamics, and MM/GBSA analyses |
| title_full | Revealing innovative JAK1 and JAK3 inhibitors: a comprehensive study utilizing QSAR, 3D-Pharmacophore screening, molecular docking, molecular dynamics, and MM/GBSA analyses |
| title_fullStr | Revealing innovative JAK1 and JAK3 inhibitors: a comprehensive study utilizing QSAR, 3D-Pharmacophore screening, molecular docking, molecular dynamics, and MM/GBSA analyses |
| title_full_unstemmed | Revealing innovative JAK1 and JAK3 inhibitors: a comprehensive study utilizing QSAR, 3D-Pharmacophore screening, molecular docking, molecular dynamics, and MM/GBSA analyses |
| title_short | Revealing innovative JAK1 and JAK3 inhibitors: a comprehensive study utilizing QSAR, 3D-Pharmacophore screening, molecular docking, molecular dynamics, and MM/GBSA analyses |
| title_sort | revealing innovative jak1 and jak3 inhibitors a comprehensive study utilizing qsar 3d pharmacophore screening molecular docking molecular dynamics and mm gbsa analyses |
| topic | Janus kinases FDA-drug cytochrome P450 rheumatoid arthritis immune system interleukin |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2024.1348277/full |
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