Acacetin and pinostrobin as a promising inhibitor of cancer-associated protein kinases. (May 2021)

• Record Type: Journal Article
• Authors: Singh, Shilpi; Meena, Ashish; Luqman, Suaib; Meena, Abha
• Is Part Of: Food and chemical toxicology. Volume 151(2021)
• Publication Date: 2021-05
• Subjects: Kinases -- Flavonoids -- Cancer -- Pinostrobin -- Acacetin -- Chemoprevention; ADMET Absorption distribution, metabolism, excretion, toxicity -- Akt/PKB protein kinase-B -- B-Raf Serine/threonine-protein kinase B-RAF -- EGFR epidermal growth factor receptor -- Fyn Non-receptor tyrosine kinase -- GI Gastrointestinal -- JAK-2 Janus kinase -- MAPK Mitogen-activated protein kinases -- MKK4 Mitogen-activated protein kinase kinase 4 -- mTOR Mammalian target of rapamycin -- Open babel Open source chemistry toolbox software -- PDB Protein data bank -- PI3K phosphatidylinositol-3 kinase -- PKC Protein kinase C -- STAT Signal transducer and activator of transcription -- TPSA Topological polar surface area -- VEGF Vascular endothelial growth factor -- Zap-70 Zeta-chain associated protein Kinase 70; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2021.112091
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Protein kinases associated with cancer genes play vital role in angiogenesis, invasion, motility, proliferation, and survival. Therefore, cancer prevention/treatment, targeting kinases with phytochemicals could be a promising approach. Given potential of phytochemicals in modulating cancer-associated kinases, present study aims to find inhibitory prospects of selected flavonoids for cancer-chemoprevention/treatment. The molecular docking interaction analysis was done by exploring binding potential of flavonoids with kinases (PI3K, Akt, mTOR, EGFR, MAPK, MKK4, Fyn, ZAP-70, B-Raf, JAK-2, STAT-1, STAT-3, STAT-4, STAT-5, and VEGF) involved in various carcinogenesis phases. Among flavonoids acacetin showed highest binding-energy against JAK-2 following Fyn > VEGF > PI3K > MKK4 > MAPK > BRaf > STAT-5 > STAT-1 > STAT-4 whereas pinostrobin depicts higher binding-energy with JAK-2 followed by B-Raf > MKK4 > VEGF > PI3K > MAPK > STAT-1 > STAT-4 > STAT-5. Further, molecular-dynamic simulation revealed that pinostrobin interacted with JAK-2 protein with binding-energy of −25.068 ± 1.08 kJ/mol whereas acacetin interacted with both JAK-2 and Fyn with binding-energies of −23.466 ± 0.9508 kJ/mol and-8.935 ± 1.3108 kJ/mol respectively. High binding-energy, low inhibition-constant, and drug-likeness of acacetin and pinostrobin provide a clue for their usage as a JAK-2 inhibitor which could be useful for molecular/cell-target based in-vitro and in-vivo investigations. Graphical abstract: Image 1 Highlights: Acacetin and pinostrobin are potential inhibitor of JAK-2. Acacetin and pinostrobin follows drug-likeness but did not show blood-brain permeability. Acacetin and pinostrobin did not inhibit the metabolic enzyme CYP2D6.