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
Affiliations
Akhtar Atiya
Department of Pharmacognosy, College of Pharmacy, King Khalid University (KKU), Guraiger St., Abha 62529, Saudi Arabia
Fahad A. Alhumaydhi
Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 52571, Saudi Arabia
Sharaf E. Sharaf
Pharmaceutical Chemistry Department, College of Pharmacy Umm Al-Qura University, Makkah 21961, Saudi Arabia
Waleed Al Abdulmonem
Department of Pathology, College of Medicine, Qassim University, P.O. Box 6655, Buraidah 51452, Saudi Arabia
Abdelbaset Mohamed Elasbali
Department of Clinical Laboratory Science, College of Applied Sciences-Qurayyat, Jouf University, Sakaka 72388, Saudi Arabia
Maher M. Al Enazi
Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam Bin Abdelaziz University, Al-Kharj 11942, Saudi Arabia
Anas Shamsi
Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman P.O. Box 346, United Arab Emirates
Talha Jawaid
Department of Pharmacology, College of Medicine, Al Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13317, Saudi Arabia
Badrah S. Alghamdi
Neuroscience Unit, Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah 22254, Saudi Arabia
Anwar M. Hashem
Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah 22254, Saudi Arabia
Ghulam Md. Ashraf
Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 22254, Saudi Arabia
Moyad Shahwan
Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman P.O. Box 346, United Arab Emirates
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.
