Molecular Docking and Molecular Dynamics Studies Reveal the Anticancer Potential of Medicinal-Plant-Derived Lignans as MDM2-P53 Interaction Inhibitors
The interaction between the tumor suppressor protein p53 and its negative regulator, the MDM2 oncogenic protein, has gained significant attention in cancer drug discovery. In this study, 120 lignans reported from Ferula sinkiangensis and <i>Justicia procumbens</i> were assessed for docki...
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| Format: | Article |
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MDPI AG
2023-09-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/18/6665 |
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| author | Tagyedeen H. Shoaib Nihal Abdelmoniem Rua M. Mukhtar Amal Th. Alqhtani Abdullah L. Alalawi Razan Alawaji Mashael S. Althubyani Shaimaa G. A. Mohamed Gamal A. Mohamed Sabrin R. M. Ibrahim Hazem G. A. Hussein Abdulrahim A. Alzain |
| author_facet | Tagyedeen H. Shoaib Nihal Abdelmoniem Rua M. Mukhtar Amal Th. Alqhtani Abdullah L. Alalawi Razan Alawaji Mashael S. Althubyani Shaimaa G. A. Mohamed Gamal A. Mohamed Sabrin R. M. Ibrahim Hazem G. A. Hussein Abdulrahim A. Alzain |
| author_sort | Tagyedeen H. Shoaib |
| collection | DOAJ |
| description | The interaction between the tumor suppressor protein p53 and its negative regulator, the MDM2 oncogenic protein, has gained significant attention in cancer drug discovery. In this study, 120 lignans reported from Ferula sinkiangensis and <i>Justicia procumbens</i> were assessed for docking simulations on the active pocket of the MDM2 crystal structure bound to Nutlin-3a. The docking analysis identified nine compounds with higher docking scores than the co-crystallized reference. Subsequent AMDET profiling revealed satisfactory pharmacokinetic and safety parameters for these natural products. Three compounds, namely, justin A, 6-hydroxy justicidin A, and 6′-hydroxy justicidin B, were selected for further investigation due to their strong binding affinities of −7.526 kcal/mol, −7.438 kcal/mol, and −7.240 kcal/mol, respectively, which surpassed the binding affinity of the reference inhibitor Nutlin-3a (−6.830 kcal/mol). To assess the stability and reliability of the binding of the candidate hits, a molecular dynamics simulation was performed over a duration of 100 ns. Remarkably, the thorough analysis demonstrated that all the hits exhibited stable molecular dynamics profiles. Based on their effective binding to MDM2, favorable pharmacokinetic properties, and molecular dynamics behavior, these compounds represent a promising starting point for further refinement. Nevertheless, it is essential to synthesize the suggested compounds and evaluate their activity through in vitro and in vivo experiments. |
| first_indexed | 2024-03-10T22:24:15Z |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T22:24:15Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-847abb685e4c43d3943f8c02d23214ec2023-11-19T12:10:41ZengMDPI AGMolecules1420-30492023-09-012818666510.3390/molecules28186665Molecular Docking and Molecular Dynamics Studies Reveal the Anticancer Potential of Medicinal-Plant-Derived Lignans as MDM2-P53 Interaction InhibitorsTagyedeen H. Shoaib0Nihal Abdelmoniem1Rua M. Mukhtar2Amal Th. Alqhtani3Abdullah L. Alalawi4Razan Alawaji5Mashael S. Althubyani6Shaimaa G. A. Mohamed7Gamal A. Mohamed8Sabrin R. M. Ibrahim9Hazem G. A. Hussein10Abdulrahim A. Alzain11Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Wad Madani 21111, SudanDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Wad Madani 21111, SudanDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Wad Madani 21111, SudanPharmaceutical Care Services, Madinah Cardiac Center, MOH, Al Madinah Al Munawwarah 11176, Saudi ArabiaPharmaceutical Care Services, King Salman Medical City, MOH, Al Madinah Al Munawwarah 11176, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Qassim 51452, Saudi ArabiaPharmaceutical Care Services, Madinah Cardiac Center, MOH, Al Madinah Al Munawwarah 11176, Saudi ArabiaFaculty of Dentistry, British University, El Sherouk City, Suez Desert Road, Cairo 11837, EgyptDepartment of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi ArabiaPreparatory Year Program, Department of Chemistry, Batterjee Medical College, Jeddah 21442, Saudi ArabiaPreparatory Year Program, Batterjee Medical College, Jeddah 21442, Saudi ArabiaDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Wad Madani 21111, SudanThe interaction between the tumor suppressor protein p53 and its negative regulator, the MDM2 oncogenic protein, has gained significant attention in cancer drug discovery. In this study, 120 lignans reported from Ferula sinkiangensis and <i>Justicia procumbens</i> were assessed for docking simulations on the active pocket of the MDM2 crystal structure bound to Nutlin-3a. The docking analysis identified nine compounds with higher docking scores than the co-crystallized reference. Subsequent AMDET profiling revealed satisfactory pharmacokinetic and safety parameters for these natural products. Three compounds, namely, justin A, 6-hydroxy justicidin A, and 6′-hydroxy justicidin B, were selected for further investigation due to their strong binding affinities of −7.526 kcal/mol, −7.438 kcal/mol, and −7.240 kcal/mol, respectively, which surpassed the binding affinity of the reference inhibitor Nutlin-3a (−6.830 kcal/mol). To assess the stability and reliability of the binding of the candidate hits, a molecular dynamics simulation was performed over a duration of 100 ns. Remarkably, the thorough analysis demonstrated that all the hits exhibited stable molecular dynamics profiles. Based on their effective binding to MDM2, favorable pharmacokinetic properties, and molecular dynamics behavior, these compounds represent a promising starting point for further refinement. Nevertheless, it is essential to synthesize the suggested compounds and evaluate their activity through in vitro and in vivo experiments.https://www.mdpi.com/1420-3049/28/18/6665cancerMDM2-P53PPIFerula sinkiangensis<i>Justicia procumbens</i>lignans |
| spellingShingle | Tagyedeen H. Shoaib Nihal Abdelmoniem Rua M. Mukhtar Amal Th. Alqhtani Abdullah L. Alalawi Razan Alawaji Mashael S. Althubyani Shaimaa G. A. Mohamed Gamal A. Mohamed Sabrin R. M. Ibrahim Hazem G. A. Hussein Abdulrahim A. Alzain Molecular Docking and Molecular Dynamics Studies Reveal the Anticancer Potential of Medicinal-Plant-Derived Lignans as MDM2-P53 Interaction Inhibitors Molecules cancer MDM2-P53 PPI Ferula sinkiangensis <i>Justicia procumbens</i> lignans |
| title | Molecular Docking and Molecular Dynamics Studies Reveal the Anticancer Potential of Medicinal-Plant-Derived Lignans as MDM2-P53 Interaction Inhibitors |
| title_full | Molecular Docking and Molecular Dynamics Studies Reveal the Anticancer Potential of Medicinal-Plant-Derived Lignans as MDM2-P53 Interaction Inhibitors |
| title_fullStr | Molecular Docking and Molecular Dynamics Studies Reveal the Anticancer Potential of Medicinal-Plant-Derived Lignans as MDM2-P53 Interaction Inhibitors |
| title_full_unstemmed | Molecular Docking and Molecular Dynamics Studies Reveal the Anticancer Potential of Medicinal-Plant-Derived Lignans as MDM2-P53 Interaction Inhibitors |
| title_short | Molecular Docking and Molecular Dynamics Studies Reveal the Anticancer Potential of Medicinal-Plant-Derived Lignans as MDM2-P53 Interaction Inhibitors |
| title_sort | molecular docking and molecular dynamics studies reveal the anticancer potential of medicinal plant derived lignans as mdm2 p53 interaction inhibitors |
| topic | cancer MDM2-P53 PPI Ferula sinkiangensis <i>Justicia procumbens</i> lignans |
| url | https://www.mdpi.com/1420-3049/28/18/6665 |
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