A computer-aided insight into the identification of significant therapeutic flavone as a promising agent for sarcopenic obesity

Abstract Polyphenols, the important secondary metabolites, consist of multiple phytochemicals and show numerous physiological effects. Flavones play a significant role in various chronic disorders such as diabetes.. In this study, all the flavones were encountered, and it was further filtered based on their drug-likeness properties and pharmacokinetic parameters. Existing literature confirms that flavone-based compounds are suitable as the drug of choice in sarcopenic obesity. A molecular docking study was performed toward the myostatin inhibition profile of the flavones using PDB:3HH2 as a target site. This computer-aided drug design helps select lead molecules in novel drug discovery. Graphical Abstract


Introduction
The age-related loss of related skeletal mass is referred to as sarcopenia.The significant decline in muscle quality is due to decreased muscle strength and function.An increase in the redisposition of body fat to the abdominal and visceral regions can have a powerful impact on health (Molino et al. 2016).The pathogenesis of sarcopenic obesity underlies the interaction between adipose tissue and muscle mass.Increased insulin resistance, with increased inflammation, can contribute to the secretion of leptin and other adipokines and cytokines, leading to sarcopenic obesity (Molino et al. 2016;Sabarathinam, Rajappan Chandra, et al. 2023;Sabarathinam, Satheesh, et al. 2023;Zamboni et al. 2019) Polyphenols, the important secondary metabolites, consist of multiple phytochemicals and show numerous physiological effects (Mutha et al. 2021) The physiological and chemical properties of flavonoids determine their absorption.They include molecular size, pKa values, lipophilicity, solubility after consumption and their configuration.Polyphenols have antidiabetic, anticancer, antioxidant, cardioprotective, neuroprotective, anti-inflammatory, antibacterial, antifungal, antiviral and hepatoprotective effects.In this study, we aimed to understand the pharmacokinetic parameters difference and the therapeutic potential of flavones towards sarcopenic obesity.

Results and discussion
Based on the literature, 37 different flavones were taken into action in this study, followed by the flavones filtered based on their drug-likeness property (Table S1).From those, 26 flavones were finalized.The pharmacokinetic parameters of the flavones were generated.S2.
The physicochemical properties of the shortlisted compounds are given in Table S3.Molecular docking analysis was performed for the selected 26 compounds with PDB:3HH2 to estimate their myostatin inhibition profile.Were Baicalein, Chalconaringenin, Quercetin, Chrysin, Morin, Phloretin, tangeretin, Cyanidin, Luteolin, Peonidin and Kaempferol reported with binding scores −8 and above (kcal/mol) followed by Catechin and Epicatechin reported with the least binding score −5.3(kcal/ mol).With this preliminary evidence, we have observed that numerous ethnobotanical analyses have recently revealed that using plant-based medicinal products as a primary active substance is a preferable starting material for many chronic illnesses, including Parkinson's and Alzheimer's diseases.Diverse classes of well-developed conventional and plant-based semi-synthetic neuroprotective agents have been identified (Vijayakumar et al. 2016) The Novel chemical entity can be identified easily by isolating them from natural materials (Katiyar et al. 2012).Physicochemical properties are the main key factors in the novel drug discovery process, which assures pharmacological activity.Plants with flavones have the genetic ability to function as natural insecticides, protecting them from insects and fungi that cause illnesses (Mierziak et al. 2014).
Hence, the present study is aimed to estimate the therapeutic potential of flavones in sarcopenic obesity.Different flavonoids exhibit antidiabetic properties differently.Diabetes and diabetes related cardiovascular complications are the major threat for many chronic illnesses.Type 2 diabetes mellitus is one of the most chronic diseases, and the incidence of pre-diabetes has been increasing due to sedentary lifestyles and irrational food diets.Effective prevention and management of diabetes can be achieved by proper food diet and physical exercise.Treatment of diabetes involves: • Early prevention of microvascular and macrovascular complications.
• Controlling blood glucose levels.
• Improving insulin production and sensitivity.
The addition of flavonoids rich food in the diabetic diet can help in the cytoprotection of pancreatic beta cells, activation of insulin signalling, and increase insulin secretion.The flavones and flavonoids also inhibit processes like glycogenolysis and gluconeogenesis (Xiao 2022).Flavones also regulate inflammatory response and oxidative stress, and insulin resistance, which are the central pathogenesis involved in Type 2 Diabetes Mellitus by numerous cellular networks such as NF-κB, PI3K/Akt, MAPK, GSK3 and PPARγ (Hussain et al. 2020).Flavones exhibit anti-oxidant properties by phosphorylation of JNK and p38 MAPKs and regulate executioner caspase 3, and also they involve in the suppression of NADPH oxidase.The above mechanism decreases the risk of diabetic cardiac myopathy.Nrf2 downregulation is observed in type 2 diabetes mellitus results in cardiac apoptosis, and it increases the risk of organ degeneration of major organ systems.upregulation of nrf2 flavonoids increases the production of significant anti-oxidants like SOD, GSH, CAT and HO-1 and inhibition of Keap-1 expression (Jubaidi et al. 2021).The hydroxyl groups and the presence of C-2-C3 double bond and ketone group at C-4 in ring C is responsible for the xanthine oxidase, alpha-glucosidase and DPP-4 inhibitory activities.The endothelial cellular stress is mainly observed in hyperglycemia patients due to the accumulation of reactive oxygen species.This release of ROS in the long term results in the impairment of microvascular endothelial cells leading to diabetic nephrosis and diabetic cardiomyopathy.Moreover, myoblast cells treated with rutin, citrus glycoside flavonoid reduced the endoplasmic reticulum stress and apoptosis.The activation of Nuclear Factor kappa B (NF-κB) in diabetic patients due to the increased oxidative stress triggers various vascular complications observed in diabetes patients.The activation of this transcription factor can initiate the expression of multiple cytokines, chemokines, and cell adhesion molecules.Baicalin, a polyphenolic flavonoid, reduced glucose levels significantly in diabetic mice by suppressing the NF-κB pathway and its inflammatory cytokines.Quercetin, flavonoids target vasoconstriction in diabetes by inhibiting the NF-κB pathway.
The AMPK pathway is essential in metabolic conditions like diabetes and leads to insulin resistance.Flavonoids are reported to regulate AMPK pathways in diabetes.Among all flavonoids, Quercetin, daidzein and kaempferol are shown to regulate the AMPK pathway.Quercetin modulated the antidiabetic effects by regulating the AMPK pathway and GLuT4 expression.Myotubes cells treated with Daidzein modulated the antidiabetic impact by regulating the phosphorylation of AMPK and translocation of GLuT4 expression.Kaempferol regulated the antidiabetic effects in pancreatic cells by upregulating the phosphorylation of the AMPK pathway.Increasing hepatic enzymes such as glucose six phosphatase or phosphoenol pyruvate carboxykinase regulates blood glucose.Flavonoids like Genistein, diosmin, morin, rutin and baicalin are reported to improve the regulation of these enzymes.They decrease these enzymes level and increase the activity of enzyme hexokinases (AL-Ishaq et al. 2022).Puerarin, a flavonoid used for treating diabetes in China, has been reported to reduce serum nitric oxide and H 2 O 2 levels by inhibiting the expressions of NOX2 and NOX4 and regulating NF-κB in diabetic rats.It is seen to control the antioxidant function by reducing oxidative stress.It is seen to downregulate ROS production, upregulate antioxidant enzyme activity, and regulates blood sugar.Quercetin, a flavonoid with antioxidant properties, has a catechol group in the B ring and an OH group at the third position of the A ring.These groups enable antioxidant activity by increasing oxidase activity and preventing lipid peroxidation.It activates the expression of PI3K and reduces the oxidative damage of β-cells by promoting insulin secretion.Similarly, Luteolin, a natural flavonoid, exhibited an antidiabetic effect by NOS/NO and Nrf2-related antioxidant pathways.Luteolin showed an increase in the level of antioxidant enzymes.Luteolin exhibited antidiabetic activity by regulating the expression of antioxidant genes regulated by Nrf2 and inhibited the expression of inflammatory cytokines.Luteolin in the study demonstrated the modulatory effect on glucose and lipid metabolism, which directly affects beta-cell function.Myricetin, a flavonoid in studies, has been shown to reduce and block oxidative stress by impacting the antioxidant enzymes.Glucagon-like peptide-1 (GLP-1) is regulated by myricetin which can be used as a potential target for increasing insulin secretion and reducing blood sugar levels.α-Amylase and α-Glu, enzymes involved in starch hydrolysis, have been targeted by myricetin in some recent studies, thereby reducing blood sugar levels (Li et al. 2022).The basic skeleton of flavone protects muscle structure and functions directly through physiological mechanisms or through distinct molecular signal pathways.Flavonoids had more significant effects on insulin resistance and also in appendicular muscle mass (Li et al. 2022).Flavones help in mitochondrial activity, myogenesis and anti-muscle atrophy (Kim and Hwang 2020).
Molecular docking was performed using selected proteins and the ligands in Autodock vina.Binding energy values are indicated in Table S4.All the docking poses showed negative binding energy, suggesting a good binding affinity with the target protein-a major Molecular docking image illustrated in Figure S1.

Conclusion
In conclusion, the current study evaluates the myostatin inhibition potential of the naturally occurring flavone molecules.In total, 36 flavones, 10 of them were filtered due to the violations.The selected 26 compounds were docked against (PDB Id: 3HH2) to evaluate their binding affinity and interactions with the binding site where −8.6 kcal/ mol [Baicalein] was found to be high and −5.3 kcal/mol [Epicatechin] was found to be the least binding affinity.This piece of evidence helps in the differentiation in the selection of lead molecules in drug discovery.However, more preclinical and clinical study is warranted.