Identification of 11-Hydroxytephrosin and Torosaflavone A as Potential Inhibitors of 3-Phosphoinositide-Dependent Protein Kinase 1 (PDPK1): Toward Anticancer Drug Discovery

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

doi:10.3390/biology11081230

Identification of 11-Hydroxytephrosin and Torosaflavone A as Potential Inhibitors of 3-Phosphoinositide-Dependent Protein Kinase 1 (PDPK1): Toward Anticancer Drug Discovery

Biology (Basel). 2022 Aug 18;11(8):1230. doi: 10.3390/biology11081230.

Authors

Akhtar Atiya¹, Fahad A Alhumaydhi², Sharaf E Sharaf^{3

4}, Waleed Al Abdulmonem⁵, Abdelbaset Mohamed Elasbali⁶, Maher M Al Enazi⁷, Anas Shamsi^{8

9}, Talha Jawaid¹⁰, Badrah S Alghamdi^{11

12}, Anwar M Hashem^{13

14}, Ghulam Md Ashraf^{12

15}, Moyad Shahwan^{8

16}

Affiliations

¹ Department of Pharmacognosy, College of Pharmacy, King Khalid University (KKU), Guraiger St., Abha 62529, Saudi Arabia.
² Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 52571, Saudi Arabia.
³ Pharmaceutical Chemistry Department, College of Pharmacy Umm Al-Qura University, Makkah 21961, Saudi Arabia.
⁴ Clinical Research Administration, Executive Administration of Research and Innovation, King Abdullah Medical City in the Holy Capital, Makkah 21955, Saudi Arabia.
⁵ Department of Pathology, College of Medicine, Qassim University, P.O. Box 6655, Buraidah 51452, Saudi Arabia.
⁶ Department of Clinical Laboratory Science, College of Applied Sciences-Qurayyat, Jouf University, Sakaka 72388, Saudi Arabia.
⁷ Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam Bin Abdelaziz University, Al-Kharj 11942, Saudi Arabia.
⁸ Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman P.O. Box 346, United Arab Emirates.
⁹ Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
¹⁰ Department of Pharmacology, College of Medicine, Al Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13317, Saudi Arabia.
¹¹ Neuroscience Unit, Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah 22254, Saudi Arabia.
¹² Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 22254, Saudi Arabia.
¹³ Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah 22254, Saudi Arabia.
¹⁴ Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 22254, Saudi Arabia.
¹⁵ Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 22254, Saudi Arabia.
¹⁶ College of Pharmacy, Ajman University, Ajman P.O. Box 346, United Arab Emirates.

Abstract

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.

Keywords: 3-phosphoinositide-dependent protein kinase 1; Indian phytoconstituents; cancer; conformational dynamics; drug discovery; virtual screening.

Abstract

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