Journal of Phytology 2021, 13: 192-202 doi: 10.25081/jp.2021.v13.7356 https://updatepublishing.com/journal/index.php/jp 192 J Phytol • 2021 • Vol 13 INTRODUCTION Oxidative stress (OS) is a condition of increased accumulation of reactive oxygen species (ROS) in the body. It is caused by the imbalance in the generation and scavenging of ROS in cells and tissues due to the inability of the biological system to detoxify them. Increased levels of ROS results in the oxidation of nucleic acids, proteins and lipids leading to irreversible damage to the cellular structures (Farías et al., 2017). Oxidative stress, directly or indirectly serves to influence the activation or deactivation of multiple signalling pathways. Thus OS plays an important role in the susceptibility of many chronic diseases (Prasad & Srivastava, 2020) like atherosclerosis (Matsuoka., 2001), renal disorders (Pawlak et al., 2009), retinal diseases (Masuda et al., 2017), cardiovascular problems (Farías et al., 2017), oral cancer (Yu et al., 2020), male infertility (Ahmad et al., 2010), neurodegenerative disorders (Shah et al., 2015) and a plethora of other diseases. As there exists a pathway crosstalk between COVID-19 and most of these comorbid conditions, they also lead to an increase in severity of COVID-19 An in silico approach towards exploration of the oxidative stress resistance of major withanolides of Withania somnifera in relation to COVID-19 management Sangeetha Vinodkumar, Krishnapriya Santhanu, Kanimozhi Natarajan, Kalaiselvi Senthil* Department of Biochemistry, Biotechnology and Bioinformatics, Avinashilingam Institute of Home Science and Higher Education for Women, Coimbatore- 641043, Tamil Nadu, India ISSN: 2075-6240 Copyright: © The authors. This article is open access and licensed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted, use, distribution and reproduction in any medium, or format for any purpose, even commercially provided the work is properly cited. Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. Research Article ABSTRACT Oxidative stress is the state of imbalance between the production of reactive oxygen species (free radicals) in the biological system and the ability of the body to detoxify them resulting in increased accumulation of free radicals in the cells. This stress leads to weakening of the immune system thus leading to higher susceptibility to other infections as well. This also includes the weakening of the respiratory tract leading to increased susceptibility of viral infections as in the case of COVID-19. Treatment for any kind of abnormality requires the identification of the key target proteins and pathways that are being altered. Withania somnifera is being used in the traditional medicinal system to improve health and longevity thus creating a sense of mental as well as physical well being. The present study utilises network pharmacological approach to predict the potential oxidative stress targets of the three major withanolides: withanolide A, withaferin A and withanone. Primarily, the targets of the individual withanolides were obtained from the Swiss target and DIGEP-pred databases and the GO terms and lead hits related to oxidative stress were retrieved from AMIGO2 database. Totally 40 correlative hits were obtained as anti stress targets of the withanolides, which were subjected to functional enrichment and protein–protein interaction analysis to study the enriched pathways underlying oxidative stress response. Further the eleven crucial targets of the four selected pathways were analysed using molecular docking analysis. A total of forty protein hits were obtained as oxidative stress targets of the withanolides. Further, the pathway enrichment of these forty target genes showed the AGE RAGE signalling pathway as highly enriched pathway. Therefore, the AGE RAGE signalling pathway along with its underlying pathways namely MAPK signalling pathway, FOXO pathway and PI3-AKT pathway were chosen among all the other enriched pathways. Further the molecular docking analysis of the eleven target proteins falling under these four pathways showed good docking scores of the withanolides with all the eleven targets with highest interaction against BCL2. From the above study, the biological targets and associated pathways of the withanolides have been retrieved. Thus the in silico approach undertaken in this study explores the role of the key withanolides in the antioxidant potential of the traditional medicinal plant Withania somnifera. KEYWORDS: Withaferin a, Oxidative stress, Pathway enrichment, Amigo2, Target prediction, Protein-protein interaction. Received: October 24, 2021 Revised: December 13, 2021 Accepted: December 17, 2021 Published: December 29, 2021 *Corresponding authors: Kalaiselvi Senthil E-mail: kalaiselvi_bc@avinuty.ac.in