Identification of 11-Hydroxytephrosin and Torosaflavone A as Potential Inhibitors of 3-Phosphoinositide-Dependent Protein Kinase 1 (PDPK1): Toward Anticancer Drug Discovery
The 3-phosphoinositide-dependent protein kinase 1 (PDPK1) has a significant role in cancer progression and metastasis as well as other inflammatory disorders, and has been proposed as a promising therapeutic target for several malignancies. In this work, we conducted a systematic virtual screening o...
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MDPI AG
2022-08-01
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| author | Akhtar Atiya Fahad A. Alhumaydhi Sharaf E. Sharaf Waleed Al Abdulmonem Abdelbaset Mohamed Elasbali Maher M. Al Enazi Anas Shamsi Talha Jawaid Badrah S. Alghamdi Anwar M. Hashem Ghulam Md. Ashraf Moyad Shahwan |
| author_facet | Akhtar Atiya Fahad A. Alhumaydhi Sharaf E. Sharaf Waleed Al Abdulmonem Abdelbaset Mohamed Elasbali Maher M. Al Enazi Anas Shamsi Talha Jawaid Badrah S. Alghamdi Anwar M. Hashem Ghulam Md. Ashraf Moyad Shahwan |
| author_sort | Akhtar Atiya |
| collection | DOAJ |
| description | The 3-phosphoinositide-dependent protein kinase 1 (PDPK1) has a significant role in cancer progression and metastasis as well as other inflammatory disorders, and has been proposed as a promising therapeutic target for several malignancies. In this work, we conducted a systematic virtual screening of natural compounds from the IMPPAT database to identify possible PDPK1 inhibitors. Primarily, the Lipinski rules, ADMET, and PAINS filter were applied and then the binding affinities, docking scores, and selectivity were carried out to find effective hits against PDPK1. Finally, we identified two natural compounds, 11-Hydroxytephrosin and Torosaflavone A, bearing substantial affinity with PDPK1. Both compounds showed drug-likeness as predicted by the ADMET analysis and their physicochemical parameters. These compounds preferentially bind to the ATP-binding pocket of PDPK1 and interact with functionally significant residues. The conformational dynamics and complex stability of PDPK1 with the selected compounds were then studied using interaction analysis and molecular dynamics (MD) simulations for 100 ns. The simulation results revealed that PDPK1 forms stable docked complexes with the elucidated compounds. The findings show that the newly discovered 11-Hydroxytephrosin and Torosaflavone A bind to PDPK1 in an ATP-competitive manner, suggesting that they could one day be used as therapeutic scaffolds against PDPK1-associated diseases including cancer. |
| first_indexed | 2024-03-09T11:52:44Z |
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| institution | Directory Open Access Journal |
| issn | 2079-7737 |
| language | English |
| last_indexed | 2024-03-09T11:52:44Z |
| publishDate | 2022-08-01 |
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| record_format | Article |
| series | Biology |
| spelling | doaj.art-adfeeeb06be24491b82f2d4fdd06fd9c2023-11-30T23:13:46ZengMDPI AGBiology2079-77372022-08-01118123010.3390/biology11081230Identification of 11-Hydroxytephrosin and Torosaflavone A as Potential Inhibitors of 3-Phosphoinositide-Dependent Protein Kinase 1 (PDPK1): Toward Anticancer Drug DiscoveryAkhtar Atiya0Fahad A. Alhumaydhi1Sharaf E. Sharaf2Waleed Al Abdulmonem3Abdelbaset Mohamed Elasbali4Maher M. Al Enazi5Anas Shamsi6Talha Jawaid7Badrah S. Alghamdi8Anwar M. Hashem9Ghulam Md. Ashraf10Moyad Shahwan11Department of Pharmacognosy, College of Pharmacy, King Khalid University (KKU), Guraiger St., Abha 62529, Saudi ArabiaDepartment of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 52571, Saudi ArabiaPharmaceutical Chemistry Department, College of Pharmacy Umm Al-Qura University, Makkah 21961, Saudi ArabiaDepartment of Pathology, College of Medicine, Qassim University, P.O. Box 6655, Buraidah 51452, Saudi ArabiaDepartment of Clinical Laboratory Science, College of Applied Sciences-Qurayyat, Jouf University, Sakaka 72388, Saudi ArabiaDepartment of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam Bin Abdelaziz University, Al-Kharj 11942, Saudi ArabiaCenter of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman P.O. Box 346, United Arab EmiratesDepartment of Pharmacology, College of Medicine, Al Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13317, Saudi ArabiaNeuroscience Unit, Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah 22254, Saudi ArabiaDepartment of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah 22254, Saudi ArabiaPre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 22254, Saudi ArabiaCenter of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman P.O. Box 346, United Arab EmiratesThe 3-phosphoinositide-dependent protein kinase 1 (PDPK1) has a significant role in cancer progression and metastasis as well as other inflammatory disorders, and has been proposed as a promising therapeutic target for several malignancies. In this work, we conducted a systematic virtual screening of natural compounds from the IMPPAT database to identify possible PDPK1 inhibitors. Primarily, the Lipinski rules, ADMET, and PAINS filter were applied and then the binding affinities, docking scores, and selectivity were carried out to find effective hits against PDPK1. Finally, we identified two natural compounds, 11-Hydroxytephrosin and Torosaflavone A, bearing substantial affinity with PDPK1. Both compounds showed drug-likeness as predicted by the ADMET analysis and their physicochemical parameters. These compounds preferentially bind to the ATP-binding pocket of PDPK1 and interact with functionally significant residues. The conformational dynamics and complex stability of PDPK1 with the selected compounds were then studied using interaction analysis and molecular dynamics (MD) simulations for 100 ns. The simulation results revealed that PDPK1 forms stable docked complexes with the elucidated compounds. The findings show that the newly discovered 11-Hydroxytephrosin and Torosaflavone A bind to PDPK1 in an ATP-competitive manner, suggesting that they could one day be used as therapeutic scaffolds against PDPK1-associated diseases including cancer.https://www.mdpi.com/2079-7737/11/8/12303-phosphoinositide-dependent protein kinase 1cancerIndian phytoconstituentsdrug discoveryvirtual screeningconformational dynamics |
| spellingShingle | Akhtar Atiya Fahad A. Alhumaydhi Sharaf E. Sharaf Waleed Al Abdulmonem Abdelbaset Mohamed Elasbali Maher M. Al Enazi Anas Shamsi Talha Jawaid Badrah S. Alghamdi Anwar M. Hashem Ghulam Md. Ashraf Moyad Shahwan Identification of 11-Hydroxytephrosin and Torosaflavone A as Potential Inhibitors of 3-Phosphoinositide-Dependent Protein Kinase 1 (PDPK1): Toward Anticancer Drug Discovery Biology 3-phosphoinositide-dependent protein kinase 1 cancer Indian phytoconstituents drug discovery virtual screening conformational dynamics |
| title | Identification of 11-Hydroxytephrosin and Torosaflavone A as Potential Inhibitors of 3-Phosphoinositide-Dependent Protein Kinase 1 (PDPK1): Toward Anticancer Drug Discovery |
| title_full | Identification of 11-Hydroxytephrosin and Torosaflavone A as Potential Inhibitors of 3-Phosphoinositide-Dependent Protein Kinase 1 (PDPK1): Toward Anticancer Drug Discovery |
| title_fullStr | Identification of 11-Hydroxytephrosin and Torosaflavone A as Potential Inhibitors of 3-Phosphoinositide-Dependent Protein Kinase 1 (PDPK1): Toward Anticancer Drug Discovery |
| title_full_unstemmed | Identification of 11-Hydroxytephrosin and Torosaflavone A as Potential Inhibitors of 3-Phosphoinositide-Dependent Protein Kinase 1 (PDPK1): Toward Anticancer Drug Discovery |
| title_short | Identification of 11-Hydroxytephrosin and Torosaflavone A as Potential Inhibitors of 3-Phosphoinositide-Dependent Protein Kinase 1 (PDPK1): Toward Anticancer Drug Discovery |
| title_sort | identification of 11 hydroxytephrosin and torosaflavone a as potential inhibitors of 3 phosphoinositide dependent protein kinase 1 pdpk1 toward anticancer drug discovery |
| topic | 3-phosphoinositide-dependent protein kinase 1 cancer Indian phytoconstituents drug discovery virtual screening conformational dynamics |
| url | https://www.mdpi.com/2079-7737/11/8/1230 |
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