Abstract
Endometriosis is a chronic inflammatory disease that occurs due to the presence of endometrial tissue outside the uterine cavity. It affects from 5% to 10% of women of reproductive age. High levels of matrix metalloproteinase (especially MMP-9) have been observed in women suffering from endometriosis. Thus, the aim of this study was to investigate the naturally anti-inflammatory compounds available from an algal source that can target the MMP-9 by various in silico approaches. The target 1L6J (Crystal structure of human matrix metalloproteinase MMP-9) structure was retrieved from the PDB database. Five compounds such as Eckol, Sargafuran, Vitamin E, Docosahexaenoic acid, Fucoidan and Elagolix were selected based on ‘Lipinski’s rule of five’ using the PubChem database. The pharmacokinetics, ADMET properties and biological activity of these compounds were predicted computationally using databases such as PreADME, SWISS-ADME, pkCSM and PASS. Comparative analysis of the bioactive compounds with the target was performed by AutoDock 4.2.6. Using LigPlot v.2.2, the target residues interacting with the compounds were visualised in a 2D manner. Based on the results, Eckol exhibited the highest binding energy value of −7.82 kcal/mol, whereas the Elagolix (control drug) showed a binding energy of −4.88 kcal. We conclude that Eckol can be a potent inhibitor of target MMP-9 with least side effects when compared to the control drug. Hence, this compound can be effectively explored by further in vitro and in vivo studies to develop more effective treatments for Endometriosis.
Highlights
Endometriosis is an estrogen-dependent gynaecological and chronic inflammatory disease which occurs due to the presence of endometrial tissue outside the uterine cavity that affects 5% to 10% of women of reproductive age, who are approximately 176 million women in the world [1,2,3]. 15% to 20% women are asymptomatic but may have severe symptoms
Nuclear factor kappaB (NFκB) and activator protein 1 (AP1) are the transcription factors that bind to the DNA of ectopic and endometriotic cells and transactivate the Matrix Metalloproteinases (MMPs)-9 which enhances the invasive phenotypes of the cells
3.1 Selection of the Ligand Compounds Elagolix, which is commonly used in treatment of moderate to severe pain associated with endometriosis was selected as a control drug in this in silico study
Summary
Among the different types of MMPs, MMP-9 [ called as Gelatinase B (GELB)] or 92 kDa type IV collagenase or 92 kDa gelatinase belong to the zincmetalloproteinase family They are involved in the degradation of the extracellular matrix [9]. The protein Tyrosine Kinase 7 (PTK7), via activation of an unidentified RPTK and Src, has been known to activate the mitogen-activated protein kinase (MAPK) [11,12] and NF-kappaB pathways [13]. These have been involved in the upregulation of MMP-9. Nuclear factor kappaB (NFκB) and activator protein 1 (AP1) are the transcription factors that bind to the DNA of ectopic and endometriotic cells and transactivate the MMP-9 which enhances the invasive phenotypes of the cells
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