Inhibitory Potential of Phytochemicals on Interleukin-6-Mediated T-Cell Reduction in COVID-19 Patients: A Computational Approach

Abstract

Background: A recent COVID-19 pandemic has resulted in a large death toll rate globally and even no cure or vaccine has been successfully employed to combat this disease. Patients have been reported with multi-organ dysfunction along with acute respiratory distress syndrome which implies a critical situation for patients and made them difficult to breathe and survive. Moreover, pathology of COVID-19 is also related to cytokine storm which indicates the elevated levels of interleukin (IL)-1, IL-6, IL-12, and IL-18 along with tumor necrosis factor (TNF)-α. Among them, the proinflammatory cytokine IL-6 has been reported to be induced via binding of severe acute respiratory syndrome coronavirus 2 (SARS)-CoV-2 to the host receptors. Methodology: Interleukin-6 blockade has been proposed to constitute novel therapeutics against COVID-19. Thus, in this study, 15 phytocompounds with known antiviral activity have been subjected to test for their inhibitory effect on IL-6. Based on the affinity prediction, top 3 compounds (isoorientin, lupeol, and andrographolide) with best scores were selected for 50 ns molecular dynamics simulation and MMGB/PBSA binding free energy analysis. Results: Three phytocompounds including isoorientin, lupeol, and andrographolide have shown strong interactions with the targeted protein IL-6 with least binding energies (−7.1 to −7.7 kcal/mol). Drug-likeness and ADMET profiles of prioritized phytocompounds are also very prominsing and can be further tested to be potential IL-6 blockers and thus benficial for COVID-19 treatment. The moelcular dynamics simulation couple with MMGB/PBSA binding free energy estimation validated conformational stability of the ligands and stronger intermolecular binding. The mean RMSD of the complexes is as: IL6-isoorientin complex (3.97 Å ± 0.77), IL6-lupeol (3.97 Å ± 0.76), and IL6-andrographolide complex (3.96 Å ± 0.77). In addition, the stability observation was affirmed by compounds mean RMSD: isoorientin (0.72 Å ± 0.32), lupeol (mean 0.38 Å ± 0.08), and andrographolide (1.09 Å ± 0.49). A similar strong agreement on systems stability was unraveled by MMGB/PBSA that found net binding net ~ −20 kcal/mol for the complexes dominated by van der Waal interaction energy. Conclusion: It has been predicted that proposing potential IL-6 inhibitors with less side effects can help critical COVID-19 patients because it may control the cytokine storm, a major responsible factor of its pathogenesis. In this study, 3 potential phytocompounds have been proposed to have inhibitory effect on IL-6 that can be tested as potential therapeutic options against SARS-CoV-2.

In Silico Study of Bioactive Compounds From Sungkai (Peronema Canescens) as Immunomodulator

“…The results of this study have better results than the research [26], where the best binding energy value obtained is-5.3 kcal/mol. Nevertheless, it exceeds the research [27] ∆G is-7.7 kcal/mol. In other research [28] ∆G is-7.3 kcal/mol.…”

In Silico Analysis Using SARS-CoV-2 Main Protease and a Set of Phytocompounds to Accelerate the Development of Therapeutic Components against COVID-19

“…Many phytocompounds have been used in traditional medicine to treat ailments possibly caused by viruses [62][63][64]. Several studies evaluated the pharmacological nature of the phytocompounds and COVID-19 proteins [65][66][67].…”

An Evaluation of the Novel Biological Properties of Diterpenes Isolated from Plectranthus ornatus Codd. In Vitro and In Silico

“…Isoorientin, a flavone C-glycoside, showed better binding affinity on IL-6, if compared to all other phytocompounds with a binding energy of −7.7 kcal/mol. Isoorientin with IL-6 interactive residues in molecular interactions were as follow: SER: 91, THR: 92, LEU: 95, PHE: 98, LEU: 140, PHE: 143, LYS: 144, LEU: 147 [ 76 ]. In addition, Prathap et al revealed that stachydrine, a pyrrolidine betaine, binds IL-6 and inhibits it, with a binding energy of −5.9 kcal/mol and hydrogen bonding with GLU: 42 [ 77 ].…”