Analysis of some flavonoids for inhibitory mechanism against cancer target phosphatidylinositol 3-kinase (PI3K) using computational tool

Mohd Suhail; Wejdan M AlZahrani; Shazi Shakil; Mohammad Tarique; Shams Tabrez; Torki A Zughaibi; Mohd Rehan

doi:10.3389/fphar.2023.1236173

Analysis of some flavonoids for inhibitory mechanism against cancer target phosphatidylinositol 3-kinase (PI3K) using computational tool

Front Pharmacol. 2023 Oct 13:14:1236173. doi: 10.3389/fphar.2023.1236173. eCollection 2023.

Authors

Mohd Suhail^{1

2}, Wejdan M AlZahrani³, Shazi Shakil^{1

2

4}, Mohammad Tarique⁵, Shams Tabrez^{1

2}, Torki A Zughaibi^{1

2}, Mohd Rehan^{1

2}

Affiliations

¹ King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.
² Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
³ Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
⁴ Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia.
⁵ Department of Child Health, School of Medicine, University of Missouri, Columbia, MO, United States.

Abstract

Cancer has been one of the leading causes of mortality worldwide over the past few years. Some progress has been made in the development of more effective cancer therapeutics, resulting in improved survival rates. However, the desired outcome in the form of successful treatment is yet to be achieved. There is high demand for the development of innovative, inexpensive, and effective anticancer treatments using natural resources. Natural compounds have been increasingly discovered and used for cancer therapy owing to their high molecular diversity, novel biofunctionality, and minimal side effects. These compounds can be utilized as chemopreventive agents because they can efficiently inhibit cell growth, control cell cycle progression, and block several tumor-promoting signaling pathways. PI3K is an important upstream protein of the PI3K-Akt-mTOR pathway and a well-established cancer therapeutic target. This study aimed to explore the small molecules, natural flavonoids, viz. quercetin, luteolin, kaempferol, genistein, wogonin, daidzein, and flavopiridol for PI3Kγ kinase activity inhibition. In this study, the binding pose, interacting residues, molecular interactions, binding energies, and dissociation constants were investigated. Our results showed that these flavonoids bound well with PI3Kγ with adequate binding strength scores and binding energy ranging from (-8.19 to -8.97 Kcal/mol). Among the explored ligands, flavopiridol showed the highest binding energy of -8.97 Kcal/mol, dock score (-44.40), and dissociation constant term, ${p K}_{d}$ of 6.58 against PI3Kγ. Based on the above results, the stability of the most promising ligand, flavopiridol, against PI3Kγ was evaluated by molecular dynamics simulations for 200 ns, confirming the stable flavopiridol and PI3Kγ complex. Our study suggests that among the selected flavonoids specifically flavopiridol may act as potential inhibitors of PI3Kγ and could be a therapeutic alternative to inhibit the PI3Kγ pathway, providing new insights into rational drug discovery research for cancer therapy.

Keywords: Cancer; PI3Kγ; drug discovery; flavonoids; flavopiridol; kinase; small molecules.

Grants and funding

The authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia for funding this research work through the project number IFPRC-097-141-2020 and King Abdulaziz University, DSR, Jeddah, Saudi Arabia.