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

Frontiers in Pharmacology

Pharmacology

Wejdan M. AlZahrani¹  Mohammad Tarique²  Torki A. Zughaibi³  Mohd Suhail³  Shams Tabrez³  Mohd Rehan³  Shazi Shakil⁴ 

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

关键词: Cancer;    small molecules;    flavonoids;    kinase;    drug discovery;    flavopiridol;    PI3Kγ;   

DOI  :  10.3389/fphar.2023.1236173

 received in 2023-06-07, accepted in 2023-10-04,  发布年份 2023

来源: Frontiers

【 摘 要 】

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, pKd 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.

【 授权许可】

Unknown   
Copyright © 2023 Suhail, AlZahrani, Shakil, Tarique, Tabrez, Zughaibi and Rehan.