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| ORIGINAL ARTICLE |
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| Year : 2022 | Volume
: 1
| Issue : 4 | Page : 255-275 |
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A comparative molecular docking study of phytocompounds in red wine for the management of coronary artery disease and diabetes
Naman Vijaykumar Jain1, Omkar Pravin Tambekar2, SL Bodhankar2, Deepali Amol Bansode1
1 Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Pune, Maharashtra, India
2 Department of Pharmacology, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Pune, Maharashtra, India
| Date of Submission | 21-Aug-2022 |
| Date of Decision | 10-Sep-2022 |
| Date of Acceptance | 24-Oct-2022 |
| Date of Web Publication | 5-Dec-2022 |
Correspondence Address:
Deepali Amol Bansode
Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Erandwane, Pune - 411 038, Maharashtra
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/jpdtsm.jpdtsm_75_22
BACKGROUND: In this study, we have investigated the binding affinity, ADME, and toxicity analysis of phytocompounds of red wine by performing molecular docking studies related to diabetes and cardioprotective activity. Our aim is to Identify the affinity of phytocompounds of red wine for the management of coronary artery disease and diabetes by performing docking.
METHODS: Molecular docking and toxicity prediction were performed using AutoDock Vina, Pymol, Discovery studio, Autodock Tools, Chemdraw, Swiss ADME, and PROTOX-II tools.
RESULTS: Docking investigations of phytocompounds in red wine with targeted proteins, such as 2ZJ3 and 5JMY, found that all selected phytocompounds had a high binding affinity and enhanced binding modes for selected target receptors, resulting in increased activity for diabetes and coronary artery disease. Gallotannin (hydrolysable tannin), the most major phytocompound found in red wine, has a high binding affinity for the 2ZJ3 protein, which is the isomerase domain of the human glucose: fructose-6-phosphate amidotransferase receptor (−11.9 Kcal/mol). Theaflavin has a binding affinity for the 5JMY protein of −11.4 Kcal/mol (neprilysin receptor). The binding affinity of all phytocompounds is depicted.
CONCLUSION: Red wine is an alcoholic beverage that contains polyphenols such as anthocyanins, flavanols, tannins, and nonflavonoid chemicals, phenolic acids, and resveratrol. These chemicals have an effect on the pharmacological qualities of red wine. Investigators are very interested in the phenolic metabolites derived from polyphenol, phenolic acids parent molecules, and this topic needs to be researched more; hence, we conclude that docking studies of phytocompounds in red wine with targeted proteins, such as 2ZJ3 and 5JMY, found that all selected phytocompounds had a high binding affinity and enhanced binding modes for selected target receptors, resulting in management of activity for diabetes and coronary artery disease. The major drawback highlights concentration-dependent intake of red wine is highlights in the in-vivo study.
Keywords: Coronary heart disease, in silico docking, polyphenols, red wine, tannins, type-II diabetes
How to cite this article:
Jain NV, Tambekar OP, Bodhankar S L, Bansode DA. A comparative molecular docking study of phytocompounds in red wine for the management of coronary artery disease and diabetes. J Prev Diagn Treat Strategies Med 2022;1:255-75 |
How to cite this URL:
Jain NV, Tambekar OP, Bodhankar S L, Bansode DA. A comparative molecular docking study of phytocompounds in red wine for the management of coronary artery disease and diabetes. J Prev Diagn Treat Strategies Med [serial online] 2022 [cited 2023 Jan 29];1:255-75. Available from: http://www.jpdtsm.com/text.asp?2022/1/4/255/362827 |
| Introduction | |  |
Molecular docking is a useful tool for predicting and studying the binding capability of protein targets and medicines. It provides precise information on the functional groups present in therapeutic compounds with which the receptor interacts, as well as a novel cohesive approach to drug design.[1] Diabetes and its complications are the leading causes of mortality in the majority of countries. Type 2 diabetes (T2D) is also known as “Non–insulin-dependent diabetes mellitus. Diabetes affects around 537 million persons aged 20–79 years. The overall number of diabetics is expected to climb to 643 million by 2030 and 783 million by 2045. Three out of every four individuals with diabetes reside in low- and middle-income nations. Almost one-half of all persons (240 million) with diabetes are undiagnosed. Diabetes claimed the lives of 6.7 million people. Diabetes accounted for at least USD 966 billion in health expenditure, accounting for 9% of total adult spending. T2D affects around 1.2 million children and adolescents aged 0–19 years. Diabetes affects one out of every six live births (21 million). A total of 541 million persons are at a higher risk of getting T2D.[2]
Coronary heart disease (CHD) and stroke are the leading causes of mortality, disability, and death.[3] The majority of CHDs are caused by atherosclerosis, a vascular degenerative process initiated by oxidative stress, and chronic inflammatory condition.[4],[5] Although excessive alcohol drinking has been linked to the development of chronic illnesses and other major difficulties, a plethora of scientific evidence suggests that moderate alcohol consumption reduces the risk of CHD.[6] Several studies show that moderate alcohol intake is related with greater levels of high-density lipoprotein cholesterol, a decreased incidence of T2D, and a reduction in lipid oxidative stress. Such epidemiological studies have shown that red wine consumption is more CHD preventative than other alcoholic drinks.[7] It is unclear whether the observed health benefits ascribed to red wine drinking are attributable only to the presence of alcohol or to the combined action of alcohol and antioxidant molecules other than alcohol found in red wine.[8],[9] In addition to alcohol, red wine includes a variety of active components known as polyphenols, which have antioxidant and anti-inflammatory effects and may help protect against atherosclerotic diseases.[10]
A number of experimental and clinical studies have been published. It reveals that the preventive effect of red wine on various pathways of the pathogenesis of a variety of diseases including cardiovascular disease and diabetes.[11],[12] Antioxidants, flavonoids, polyphenols, acids, and tannins are the first naturally occurring substances in red wine that have been shown to have positive effects in a variety of disorders, such as inhibiting low-density lipoprotein (LDL) oxidation or attenuating ischemia-reperfusion damage.[13]
All ailments and diseases involve biological processes such as cell-to-cell interaction, brain transmission, and so on, which are difficult to explain and obtain precise findings for. As a result, treating diabetes and CHD without causing harm is still a promising venture in the medical field. The investigations for simulating them in the wet lab are in vivo and in vitro research; however, in silico (computer aided) methods do not require animal models or enzymatic methods. In silico approaches have lately gained widespread acceptance and have become an essential component of industry and academic research aimed at drug design and discovery. Bioinformatics is the result of the synergistic interaction of computer science and information technology in the medical area. Bioinformatics research fields include sequence alignment, gene discovery, drug structure design, drug discovery, protein structure alignment, and so on. The basic objective of this article is to outline the numerous components of red wine and their cardioprotective as well as antidiabetic potential.
This research provides an overview of an in silico approach to phytocompounds of acting as inhibitors or agonists on the protein target 2ZJ3 associated with diabetes mellitus and 5JMY which is neprilysin (NEP) receptor. Binding energy was used to calculate the docking of the ligand with the targets (more negative the energy, more the binding).
| Materials and Methods | | |
Selection, construction, and root detection of phytocompounds
Red wine is well recognized for its cardiovascular and antidiabetic properties.[14],[15] Red wine includes a variety of polyphenols, tannins, stilbenes, and phenolic acids that have long been used to treat cyclic vomiting syndrome problems and diabetic control. Hence, after doing extensive literature research, we gathered important phytocompounds found in red wine.[10],[16] All structure phytocompounds were received in SDF format from PubChem and converted to PDB format using the Open Babel program.[17] The ligands were obtained in the following formats: XML, SDF, JSON, and ASN.1. The rotatable bonds were then allocated to PDB ligands using the AutoDock tool.[18],[19] Selected phytocompounds of red wine are mentioned in [Table 2].
Selection, initialization, and active site prediction of receptors
Receptors were chosen from extensive literatures on diabetes and coronary artery disease, and 2ZJ3 for diabetes mellitus and 5JMY for coronary artery disease were employed for the in silico investigation.[20],[21] As a result, the RCSB protein data bank (http://www.pdb.org) was used to choose these protein databases.[22] To examine molecular interaction and optimal structure, automated molecular docking was done using the docking program AutoDock Vina. The file had no heteroatoms, water molecules, or symmetry requirements. Polar hydrogens were introduced into each protein, and the effects were minimized using Kollman's partial atomic charges. PDBQT format was used to save the compressed structure.[23] The AutoDock program was used to generate a grid parameter file for protein active site prediction. A grid-box was built to cover the whole protein binding site, allowing all ligands to move freely inside it. The structure was utilized to determine the center of the active binding site, which was then employed as the grid-center box.
PDB ID
- 2ZJ3: Isomerase domain of human glucose: fructose-6-phosphate amidotransferase which is a rate-limiting enzyme in the hexosamine biosynthetic pathway and plays an important role in T2D
- 5JMY: NEP receptor complexed with LBQ657 sacubitril is an ethyl ester prodrug of LBQ657, the active NEP inhibitor, and a component of LCZ696 (sacubitril/valsartan).
ADME and toxicity study
Absorption, distribution, metabolism, excretion, and toxicity (ADMET) screening of ligands assists in assessing their absorption, toxicity, and drug-likeness. For ADMET screening, SWISSADME (Molecular modeling Group of the swiss institute of bioinformatics, Lausanne, Switzerland),[24] ADMETSAR (Laboratory of Molecular Modelling and Design, Shanghai, China), and PROTOX webservers (Charite University of Medicine, Institute of Bioinformatics) were used. SWISSADME is a web-based tool for assessing a chemical's ADME and pharmacokinetic characteristics.[25],[26]
Experimental protocol
Grid box settings
- 2ZJ3: Targeted docking grid box used in this analysis with the center of set at X = 62.787, Y = 21.248, and Z = 13.31 and spacing of 0.514A° and dimension X = 126, Y = 126, and Z = 126. Offsets of Y center is − 3.333
- 5JMY: Targeted docking grid box used in this analysis with the center of set at X = −14.601, Y = −19.893, and Z = −31.564 and spacing of 0.992A° and dimension X = 88, Y = 120, and Z = 96.
Interactive method of ligand and receptor (molecular docking)
For interaction, AutoDock 4.2.6 and AutoDock Vina 1.1.2 were used. Using AutoDock MGL tools, the receptor and ligands were converted to PDBQT format.[27],[28] After being converted to PDBQT format, the receptor structure was colored gray. After that, PDBQT files were used for molecular docking. The output was divided using AutoDock Vina split. The grid box's dimensions were determined by the structure's specs. Following the completion of the docking process, the most stable confirmation was chosen for further inspection. The discovery studio discovered H bonds, pi-pi bonds, aromatic H bonds, electrostatic interactions, amino acids, and bond lengths.[29],[30]
| Results | | |
Molecular docking
Docking investigations of phytocompounds in red wine with targeted proteins, such as 2ZJ3 and 5JMY, found that all selected phytocompounds had a high binding affinity and enhanced binding modes for selected target receptors, resulting in increased activity for diabetes and coronary artery disease. Gallotannin (hydrolysable tannin), the most major phytocompound found in red wine, has a high binding affinity for the 2ZJ3 protein, which is the isomerase domain of the human glucose: fructose-6-phosphate amidotransferase receptor (−11.9 Kcal/mol). Theaflavin has a binding affinity for the 5JMY protein of −11.4 Kcal/mol (NEP receptor) [Figure 1]. The binding affinity of all phytocompounds is depicted in [Table 1]. | Figure 1: Binding energy graph of gallotannin and theaflavin with both receptors
Click here to view |
 | Table 1: Binding energy of phytocompounds against 2ZJ3 and 5JMY was expressed in terms of kcal/mol
Click here to view |
Prediction of Lipinski's rule of 5
Drug-likeness filters aid in early preclinical development by preventing costly late-stage preclinical and clinical failure. The drug-likeness qualities of molecules were examined using the Lipinski's rule of five, and all of the chosen phytocompounds met Lipinski's rule of five which are depicted in [Table 3].
Pharmacokinetic and toxicity analysis
The PROTOX-II server was used to assess the toxicity of phytocompounds.[31] The ADMETSAR service calculates chemical pharmacokinetic parameters based on four criteria: absorption, distribution, metabolism, and excretion. The ADME analysis of flavonoids was performed using the online Swiss ADME tool on the basis of smiles. The results indicated that the values are substantial, suggesting that all compounds are suitable. Pharmacokinetic analysis and toxicity prediction are shown in [Table 4].
| Discussion | | |
Three-dimensional and two-dimensional visualization of all the interaction of ligand and receptor are shown as follows:
- Visualization of phytocompounds docked with 2ZJ3 protein: [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16], [Figure 17], [Figure 18], [Figure 19], [Figure 20]
- Visualization of phytocompounds docked with 5JMY protein: [Figure 21], [Figure 22], [Figure 23], [Figure 24], [Figure 25], [Figure 26], [Figure 27], [Figure 28], [Figure 29], [Figure 30], [Figure 31], [Figure 32], [Figure 33], [Figure 34], [Figure 35], [Figure 36], [Figure 37], [Figure 38], [Figure 39].
Red wine for therapeutic purposes in human health
A substantial amount of research has documented the health advantages of moderate red wine drinking. Several researches have been published in recent years on the association between moderate red wine intake and human health. Human and animal researches conducted over the last several decades have shown that red wine polyphenols protect against cardiovascular disease, Alzheimer's disease, breast cancer, atherosclerosis, lipid peroxidation, and inflammatory illnesses. According to a recent study, moderate wine drinking promotes the expression of critical longevity-associated genes such as p53, sirtuin1, catalase, and superoxide dismutase in humans. Resveratrol and flavonoid compounds in red wine were found to be effective in preventing CHD and to have other cardioprotective properties such as changing lipid profiles, lowering insulin resistance, reducing oxidative stress in low-LDL cholesterol, and increasing nitric oxide bioactivity. Red wine also enhanced blood pressure lowering and decreased oxidation of low-LDLs. Due to the bioactivities of phytochemicals such as lignans, quercetin, resveratrol, and flavonoids, several studies have shown that moderate red wine drinking decreases the risk of major cancer illnesses of human organs such as the esophagus, stomach, intestines, liver, and pancreas. Moderate red wine consumption is related with decreased glucose levels and plasma insulin levels in T2D patients. Several studies have revealed that moderate red wine consumption is associated with a lower risk of neurological illnesses such as Alzheimer's, Parkinson's disease, and dementia. Several mechanisms have been proposed for this neuroprotective effect, including tau and b-amyloid aggregation reduction, activation of brain-derived neurotrophic factor, and an increase in insulin-like growth factor-I, a list of several ailments whose risk is reduced by red wine consumption.
Acknowledgments
The authors acknowledge Poona College of Pharmacy, Erandwane, Pune, for providing research facilities.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16], [Figure 17], [Figure 18], [Figure 19], [Figure 20], [Figure 21], [Figure 22], [Figure 23], [Figure 24], [Figure 25], [Figure 26], [Figure 27], [Figure 28], [Figure 29], [Figure 30], [Figure 31], [Figure 32], [Figure 33], [Figure 34], [Figure 35], [Figure 36], [Figure 37], [Figure 38], [Figure 39]
[Table 1], [Table 2], [Table 3], [Table 4]
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