In Silico Molecular Docking Studies of Phenolic Compounds in Cucumis melo L. Seeds as Potential Inhibitors of Myeloperoxidase

In Silico Molecular Docking Studies of Phenolic Compounds in Cucumis melo L. Seeds as Potential Inhibitors of Myeloperoxidase
Mohammadreza Forouharmanesh,^1,* Hossein Ameri Shahrabi,²
Introduction: Myeloperoxidase (MPO) as an inflammation and oxidative stress maker is one of the main heme peroxidase enzyme involved in the acute and chronic inflammatory diseases promotes oxidative stress and mainly expressed by activated neutrophils, monocytes and selected tissue macrophages. MPO and its downstream inflammatory pathways present potential targets for discovery and development of therapeutic drugs for cardiovascular diseases, inflammatory diseases, kidney and liver diseases, immune-mediated diseases and neurodegenerative diseases. Discovery and development of bioactive natural compounds that can efficiently inhibit MPO activity to subsequently decrease inflammatory events has been focus of the current research interest. Natural compounds that have been used traditionally as nutrition or medicine may also act as anti-inflammatory agents. Cucumis melo L. belongs to Cucurbitaceae family is one of most widely consumed vegetable with remarkable economic, nutritional and medicinal values. Phenolic compositions of functional bioactive components of melon seeds possess therapeutic effects such as antioxidant, anti-inflammatory, and analgesic properties. The aim of this study was to analyze the potential MPO inhibitory activity of natural compounds in Cucumis melo L by computational docking studies.
Methods: The initial structure for the molecular docking of MPO with phenolic compounds was obtained from RCSB PDB (https://rcsb.org). The x-ray crystallography structure of human MPO with the 5FIW PDB ID was downloaded. UCSF Chimera 1.11.2 was used for preparing the receptor for docking by removing its ligands, ions and water molecules. The chemical structures of the 10 natural compounds and triazolopyrimidine a chemical inhibitor of MPO as control were retrieved from PubChem compound database. The ligands structures were prepared by ChemBioDraw and MOL SDF format of them for generating the atomic coordinates were converted to PDBQT file using PyRx tool. The ligand binding site of MPO was predicted using 3DLigandSite server. The docking experiments were performed using AutoDock 4.2.6 for docking of the ligands to grids describing the MPO as a target. We used AutoGrid for pre-calculating these grids as well as AutoDock graphical user interface called AutoDockTools (ADT) for setting up, running and analyzing the docking experiments.
Results: As assessed from literature search, 10 phenolic compounds from Cucumis melo L. including gallic acid, procatechuic acid, chlorogenic acid, vanillic acid, rosmarinic acid, luteolin, apigenin, flavone, amentoflavone and hydroxytyrosol were selected for molecular docking studies. The principle interactions of these natural compounds and MPO were revealed by molecular docking. The principle amino acid residues associated with ligand binding were revealed by active site analysis. Docking studies against MPO revealed that all phenolic compounds form H-bonds with MPO. Gallic acid interacted with MPO by forming two hydrogen bonds. All ligands were suitably docked on MPO macromolecule (−5.31 to −6.41kcal/mol) with promising score. The results have indicated that among these 10 natural compounds in Cucumis melo L., gallic acid showed higher binding affinity compared to others with the lowest binding energy (-6.41kcal/mol) and the favorable pose in active site of MPO and probably potential anti-inflammatory effect. Triazolopyrimidine showed -6.08kcal/mol binding energy. The docking site of these natural compounds and triazolopyrimidine were noteworthy similar.
Conclusion: Our findings demonstrate the potency of phenolic compounds of Cucumis melo L.seeds for discovery and development of new MPO inhibitors with less toxicity and more selectivity than chemical inhibitor and prove that dietary antioxidants like melon can be effective for treatment of a number of pathologies with compelling evidence in initiation and progression of inflammatory events. Since the binding energies of natural compounds of melon studied herein were comparable to chemical MPO inhibitor, these computational preliminary results need experimental confirmation in near future to generation of novel drugs for numerous inflammatory pathologies.
Keywords: Molecular docking, Myeloperoxidase, Cucumis melo L., Natural inhibitor, Inflammation