Abstract
Buah Merah, a typical fruit from Papua, Indonesia which is used empirically in cancer therapy is rich in carotenoids and flavonoids. However, the mechanisms by which Buah Merah ameliorates cancer remained unknown. Natural antioxidant enzymes and pro-oxidant enzymes modulation significantly suppressed ROS production and cancer growth. Therefore, the determination of target enzymes of Buah Merah contents was studied through an in silico approach. Carotenoid and flavonoid compounds from Buah Merah were docked to 7 ROS modulating enzymes using Autodock Vina and the interaction stability was studied using the CABS Flex 2.0 server. The crucial amino acids of each enzyme were determined using DockFlin and prediction of acute oral toxicity of each test ligand was studied using ProTox-II. Based on the molecular docking results, quercetin 3'-glucoside is the most potent compound in binding to CAT, GR, GPx, SOD, LOX, and NOX with binding energy values of -11.2, -9.7, -8.6, -10.2, -10.7, and -12.8 kcal/mol, respectively. Meanwhile, taxifolin 3-O-α-arabinopyranose produced the highest binding affinity of -10.0 kcal/mol at the XO. Each test ligand formed stable interactions with ROS modulating enzymes and formed bonds with crucial amino acids resulting in strong adhesion compared to native and reference ligands. The glucoside group of quercetin 3'-glucoside plays an essential role in determining the proper position in the attachment and supports the formation of hydrogen bonds with receptors. With low acute oral toxicity, it can be concluded that quercetin 3'-glucoside from Buah Merah is a potent oxidative stress modulator in cancer prevention and therapy.
Highlights
IntroductionOxidative stress results from an imbalance between the number of free radicals (ROS) and reactive metabolites (antioxidants) in the body
Oxidative stress results from an imbalance between the number of free radicals (ROS) and reactive metabolites in the body
Ligand Preparation The test compounds from Buah Merah consisted of a total of 8 carotenoids (5,6diepicapsokarpoxanthin, capsorubin, capsanthin 5,6-epoxide, capsanthin 3,6-epoxide, capsanthin, cryptocapsin, β-cryptoxanthin 5,6-epoxide, and cryptoxanthin) and a total of 8 flavonoids (4’,6,6’,8tetrahydroxy-3-methoxy-flavon, 3,4',5-trihydroxy7,3'-dimethoxy flavon, taxifolin 3-O-αarabinopyranose, quercetin 3-O-glucose, quercetin 3-methyl-ether, quercetin, taxifolin, and quercetin 3’-glucoside)
Summary
Oxidative stress results from an imbalance between the number of free radicals (ROS) and reactive metabolites (antioxidants) in the body. High levels of ROS can increase the oxidation process in normal cells, causing damage. Lipoxygenase (LOX), NADPH oxidase (NOX), and xanthine oxidase (XO) are enzymes that play a role in modulating the production of ROS. Inhibition of these three enzymes will significantly suppress ROS production and cancer growth (Bishayee and Khuda-Bukhsh, 2013; Landry and Cotter, 2014; Meitzler et al, 2014; Subramanian, Mendez and Becerra, 2016; Gào and Schöttker, 2017; Oh et al, 2019). Activation of the catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx), and superoxide dismutase (SOD) can reduce ROS levels and prevent cell damage (Goh et al, 2011; Bauer, 2012; Glorieux and Calderon, 2018; Wang et al, 2018; Chen et al, 2019; Kennedy et al, 2020)
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