Title:AI-driven Discovery of Celecoxib and Dexamethasone for Exploring their Mode of Action as Human Interleukin (IL-6) Inhibitors to Treat COVID-19-induced Cytokine Storm in Humans
Volume: 29
Issue: 34
Author(s): Israa M. Shamkh*, Mahmoud Elkazzaz, Enas. S. Radwan, Jawayria Najeeb, Md. Tabish Rehman, Mohamed F. AlAjmi, Moayad Shahwan, Muhammad Sufyan, Nouf Khalifa Alaqeel, Ibrahim A. Ibrahim, Basit Jabbar, Mohammad Shahbaz Khan, Tomasz M. Karpiński, Abdullah Haikal*, Reem M. Aljowaie, Saeedah Musaed Almutairi and Amr Ahmed
Affiliation:
- Chemo and Bioinformatics Lab, Bio Search Research Institution BSRI, Giza 12613, Egypt
- Department of Pharmacognosy,
Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
Keywords:
COVID-19, interleukin-6, celecoxib, dexamethasone, molecular docking, molecular dynamics simulation.
Abstract:
Background: In the case of COVID-19 patients, it has been observed that the immune system of
the infected person exhibits an extreme inflammatory response known as cytokine release syndrome (CRS)
where the inflammatory cytokines are swiftly produced in quite large amounts in response to infective stimuli.
Numerous case studies of COVID-19 patients with severe symptoms have documented the presence of higher
plasma concentrations of human interleukin-6 (IL-6), which suggests that IL-6 is a crucial factor in the pathophysiology
of the disease. In order to prevent CRS in COVID-19 patients, the drugs that can exhibit binding
interactions with IL-6 and block the signaling pathways to decrease the IL-6 activity may be repurposed.
Methods: This research work focused on molecular docking-based screening of the drugs celecoxib (CXB)
and dexamethasone (DME) to explore their potential to interact with the binding sites of IL-6 protein and reduce
the hyper-activation of IL-6 in the infected personnel.
Results: Both of the drugs were observed to bind with the IL-6 (IL-6 receptor alpha chain) and IL-6Rα receptor
with the respective affinities of -7.3 kcal/mol and -6.3 kcal/mol, respectively, for CXB and DME. Moreover,
various types of binding interactions of the drugs with the target proteins were also observed in the docking
studies. The dynamic behaviors of IL-6/IL-6Rα in complex with the drugs were also explored through molecular
dynamics simulation analysis. The results indicated significant stabilities of the acquired drug-protein
complexes up to 100 ns.
Conclusion: The findings of this study have suggested the potential of the drugs studied to be utilized as antagonists
for countering CRS in COVID-19 ailment. This study presents the studied drugs as promising candidates
both for the clinical and pre-clinical treatment of COVID-19.
