In silico screening and ADMET Studies of natural potential inhibitors against Myeloperoxidase from Cucumis melo L. Seeds with antioxidant and anti-inflammatory effects
In silico screening and ADMET Studies of natural potential inhibitors against Myeloperoxidase from Cucumis melo L. Seeds with antioxidant and anti-inflammatory effects
Introduction: Circulating neutrophils, monocytes and some tissue macrophages expressed Myeloperoxidase (MPO) a haem peroxidase-cyclooxygenase enzyme with vital antimicrobial and antiviral role by oxidizing halide and pseudohalide ions by H2O2. MPO-derived oxidants as a consequence of MPO discharging outside the phagocytes, lead to cardiovascular diseases, inflammatory diseases, neurodegenerative diseases, kidney diseases, and immune-mediated diseases. Therefore, MPO presents a critical target for design and development of inhibitors with therapeutic effects for these diseases. Medicinal plant-based compounds with great enzyme inhibitory effects have potential to investigate for drug design. Cucurbitaceae family members like Cucumis melo L. are proposed as highly valuable fruits serve as nutrition or medicine. The seeds of melon as by-products or waste contain phenolic compounds with potential antioxidant and anti-inflammatory properties. These natural inhibitors have great potency to develop as therapeutic agents for cancer or inflammatory diseases. In the current study, the activity of 6 natural compounds in seeds of melon as MPO potential inhibitor was analyzed by in silico studies.
Methods: The x-ray crystallography structure of human MPO with 5FIW PDB ID was obtained from RCSB PDB (https://rcsb.org) for in silico studies. PrankWeb (http://prankweb.cz/) was used for predicting and visualizing the ligand binding site of MPO. For ligand preparation, first, the chemical structures of natural compounds from seeds of melon were retrieved from PubChem compound database, following their structures were prepared by ChemBioDraw, and then PyRx tool converted the MOL SDF format to PDBQT file. Then, MPO as a receptor enzyme and natural phenolic compounds as ligands were prepared for molecular docking. The molecular docking was done using AutoDock 4.2.6 with the help of AutoGrid for the grids computation and AutoDockTools (ADT) for docking run and analysis. Then, the 3D structures of MPO-natural compounds generated by molecular docking were analyzed by further computational investigations. LIGPLOT v.4.5.3 was used to generate 2D schematic diagrams of MPO-natural compounds interactions to study the protein-ligand interactions map. Absorption, distribution, metabolism, excretion and toxicity (ADMET) parameters of natural compounds including physicochemical descriptors, pharmacokinetics properties, and the druglikeness were evaluated by ADMETlab 2.0 (https://admetmesh.scbdd.com/) and SwissADME (http://www.swissadme.ch/). Also, eMolTox webserver (http://xundrug.cn/moltox) was utilized for the prediction of potential toxicity of our investigated compounds by machine learning methods.
Results: From literature search, we selected 6 natural compounds including ellagic acid, catechin, quercetin, vanillin, eugenol, and caffeic acid extracted from Cucumis melo L. seeds as potential MPO inhibitors with phenolic property for in silico screening and ADMET analysis. First, PrankWeb predicted the critical residues of MPO in ligand binding site. These leading residues were used for obtaining site specific molecular docking results. All these phenolic compounds form Cucumis melo L. seeds showed great docking results with binding energy between -4.9 to -7.2 kcal/mol. Molecular docking results showed that among these 6 natural compounds catechin with the lowest binding energy (-7.2 kcal/mol) showed the higher binding affinity and a proper binding pose in MPO ligand binding site. 2D maps generated by LIGPLOT revealed that the hydrogen bonds played essential roles in MPO-natural compounds interactions. The predicted ADMET parameters for these phenolic compounds like solubility, LogD, LogP were acceptable with no mutagenic and carcinogenic effects. All these compounds were predicted as non-toxic by eMolTox web-server
Conclusion: Our in silico screening and ADMET analysis showed the potency of plant-based natural compounds from Cucumis melo L. seeds with antioxidant and anti-inflammatory properties to act as new MPO inhibitors with high affinity to MPO binding site, no toxicity, and acceptable ADMET parameters. This computational analysis needs more computational and experimental studies for development of new therapeutic agents for cancers or inflammatory diseases.
Keywords: Myeloperoxidase, Cucumis melo L., Natural inhibitor, ADMET, Drug design