Design of Novel Phosphatidylinositol 3-Kinase Inhibitors for Non-Hodgkin’s Lymphoma: Molecular Docking, Molecular Dynamics, and Density Functional Theory Studies on Gold Nanoparticles
Non-Hodgkin’s lymphomas are a diverse collection of lymphoproliferative cancers that are much less predictable than Hodgkin’s lymphomas with a far greater tendency to metastasize to extranodal sites. A quarter of non-Hodgkin’s lymphoma cases develop at extranodal sites and the majority of them invol...
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MDPI AG
2023-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/5/2289 |
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| author | Abdalrahim M. Ali Alaa A. Makki Walaa Ibraheem Mohammed Abdelrahman Wadah Osman Asmaa E. Sherif Ahmed Ashour Sabrin R. M. Ibrahim Kholoud F. Ghazawi Waad A. Samman Abdulrahim A. Alzain |
| author_facet | Abdalrahim M. Ali Alaa A. Makki Walaa Ibraheem Mohammed Abdelrahman Wadah Osman Asmaa E. Sherif Ahmed Ashour Sabrin R. M. Ibrahim Kholoud F. Ghazawi Waad A. Samman Abdulrahim A. Alzain |
| author_sort | Abdalrahim M. Ali |
| collection | DOAJ |
| description | Non-Hodgkin’s lymphomas are a diverse collection of lymphoproliferative cancers that are much less predictable than Hodgkin’s lymphomas with a far greater tendency to metastasize to extranodal sites. A quarter of non-Hodgkin’s lymphoma cases develop at extranodal sites and the majority of them involve nodal and extranodal sites. The most common subtypes include follicular lymphoma, chronic/small lymphocytic leukaemia, mantel cell lymphoma, and marginal zone lymphoma. Umbralisib is one of the latest PI3Kδ inhibitors in clinical trials for several hematologic cancer indications. In this study, new umbralisib analogues were designed and docked to the active site of PI3Kδ, the main target of the phosphoinositol-3-kinase/Akt/mammalian target of the rapamycin pathway (PI3K/AKT/mTOR). This study resulted in eleven candidates, with strong binding to PI3Kδ with a docking score between −7.66 and −8.42 Kcal/mol. The docking analysis of ligand–receptor interactions between umbralisib analogues bound to PI3K showed that their interactions were mainly controlled by hydrophobic interactions and, to a lesser extent, by hydrogen bonding. In addition, the MM-GBSA binding free energy was calculated. Analogue 306 showed the highest free energy of binding with −52.22 Kcal/mol. To identify the structural changes and the complexes’ stability of proposed ligands, molecular dynamic simulation was used. Based on this research finding, the best-designed analogue, analogue 306, formed a stable ligand–protein complex. In addition, pharmacokinetics and toxicity analysis using the QikProp tool demonstrated that analogue 306 had good absorption, distribution, metabolism, and excretion properties. Additionally, it has a promising predicted profile in immune toxicity, carcinogenicity, and cytotoxicity. In addition, analogue 306 had stable interactions with gold nanoparticles that have been studied using density functional theory calculations. The best interaction with gold was observed at the oxygen atom number 5 with −29.42 Kcal/mol. Further in vitro and in vivo investigations are recommended to be carried out to verify the anticancer activity of this analogue. |
| first_indexed | 2024-03-11T07:16:22Z |
| format | Article |
| id | doaj.art-43e82ed9dd3a49ebb431fb18fa4b3227 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T07:16:22Z |
| publishDate | 2023-03-01 |
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| series | Molecules |
| spelling | doaj.art-43e82ed9dd3a49ebb431fb18fa4b32272023-11-17T08:14:41ZengMDPI AGMolecules1420-30492023-03-01285228910.3390/molecules28052289Design of Novel Phosphatidylinositol 3-Kinase Inhibitors for Non-Hodgkin’s Lymphoma: Molecular Docking, Molecular Dynamics, and Density Functional Theory Studies on Gold NanoparticlesAbdalrahim M. Ali0Alaa A. Makki1Walaa Ibraheem2Mohammed Abdelrahman3Wadah Osman4Asmaa E. Sherif5Ahmed Ashour6Sabrin R. M. Ibrahim7Kholoud F. Ghazawi8Waad A. Samman9Abdulrahim A. Alzain10Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira 12217, SudanDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira 12217, SudanDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira 12217, SudanDepartment of Pharmaceutics, Faculty of Pharmacy, University of Gezira, Gezira 12217, SudanDepartment of Pharmacognosy, Faculty of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-kharj 11942, Saudi ArabiaDepartment of Pharmacognosy, Faculty of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-kharj 11942, Saudi ArabiaDepartment of Pharmacognosy, Faculty of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-kharj 11942, Saudi ArabiaPreparatory Year Program, Department of Chemistry, Batterjee Medical College, Jeddah 21442, Saudi ArabiaClinical Pharmacy Department, College of Pharmacy, Umm Al-Qura University, Makkah 24382, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawwarah 30078, Saudi ArabiaDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira 12217, SudanNon-Hodgkin’s lymphomas are a diverse collection of lymphoproliferative cancers that are much less predictable than Hodgkin’s lymphomas with a far greater tendency to metastasize to extranodal sites. A quarter of non-Hodgkin’s lymphoma cases develop at extranodal sites and the majority of them involve nodal and extranodal sites. The most common subtypes include follicular lymphoma, chronic/small lymphocytic leukaemia, mantel cell lymphoma, and marginal zone lymphoma. Umbralisib is one of the latest PI3Kδ inhibitors in clinical trials for several hematologic cancer indications. In this study, new umbralisib analogues were designed and docked to the active site of PI3Kδ, the main target of the phosphoinositol-3-kinase/Akt/mammalian target of the rapamycin pathway (PI3K/AKT/mTOR). This study resulted in eleven candidates, with strong binding to PI3Kδ with a docking score between −7.66 and −8.42 Kcal/mol. The docking analysis of ligand–receptor interactions between umbralisib analogues bound to PI3K showed that their interactions were mainly controlled by hydrophobic interactions and, to a lesser extent, by hydrogen bonding. In addition, the MM-GBSA binding free energy was calculated. Analogue 306 showed the highest free energy of binding with −52.22 Kcal/mol. To identify the structural changes and the complexes’ stability of proposed ligands, molecular dynamic simulation was used. Based on this research finding, the best-designed analogue, analogue 306, formed a stable ligand–protein complex. In addition, pharmacokinetics and toxicity analysis using the QikProp tool demonstrated that analogue 306 had good absorption, distribution, metabolism, and excretion properties. Additionally, it has a promising predicted profile in immune toxicity, carcinogenicity, and cytotoxicity. In addition, analogue 306 had stable interactions with gold nanoparticles that have been studied using density functional theory calculations. The best interaction with gold was observed at the oxygen atom number 5 with −29.42 Kcal/mol. Further in vitro and in vivo investigations are recommended to be carried out to verify the anticancer activity of this analogue.https://www.mdpi.com/1420-3049/28/5/2289cancerpi3kumbralisib analoguesmolecular dockingmolecular dynamicsgold nanoparticles |
| spellingShingle | Abdalrahim M. Ali Alaa A. Makki Walaa Ibraheem Mohammed Abdelrahman Wadah Osman Asmaa E. Sherif Ahmed Ashour Sabrin R. M. Ibrahim Kholoud F. Ghazawi Waad A. Samman Abdulrahim A. Alzain Design of Novel Phosphatidylinositol 3-Kinase Inhibitors for Non-Hodgkin’s Lymphoma: Molecular Docking, Molecular Dynamics, and Density Functional Theory Studies on Gold Nanoparticles Molecules cancer pi3k umbralisib analogues molecular docking molecular dynamics gold nanoparticles |
| title | Design of Novel Phosphatidylinositol 3-Kinase Inhibitors for Non-Hodgkin’s Lymphoma: Molecular Docking, Molecular Dynamics, and Density Functional Theory Studies on Gold Nanoparticles |
| title_full | Design of Novel Phosphatidylinositol 3-Kinase Inhibitors for Non-Hodgkin’s Lymphoma: Molecular Docking, Molecular Dynamics, and Density Functional Theory Studies on Gold Nanoparticles |
| title_fullStr | Design of Novel Phosphatidylinositol 3-Kinase Inhibitors for Non-Hodgkin’s Lymphoma: Molecular Docking, Molecular Dynamics, and Density Functional Theory Studies on Gold Nanoparticles |
| title_full_unstemmed | Design of Novel Phosphatidylinositol 3-Kinase Inhibitors for Non-Hodgkin’s Lymphoma: Molecular Docking, Molecular Dynamics, and Density Functional Theory Studies on Gold Nanoparticles |
| title_short | Design of Novel Phosphatidylinositol 3-Kinase Inhibitors for Non-Hodgkin’s Lymphoma: Molecular Docking, Molecular Dynamics, and Density Functional Theory Studies on Gold Nanoparticles |
| title_sort | design of novel phosphatidylinositol 3 kinase inhibitors for non hodgkin s lymphoma molecular docking molecular dynamics and density functional theory studies on gold nanoparticles |
| topic | cancer pi3k umbralisib analogues molecular docking molecular dynamics gold nanoparticles |
| url | https://www.mdpi.com/1420-3049/28/5/2289 |
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