Carotenoids as potential inhibitors of TNFα in COVID-۱۹ treatment

Tumor necrosis factor-alpha (TNF-α) is a multifunctional pro-inflammatory cytokine, responsible forautoimmune and inflammatory disorders. In COVID-۱۹ patients, increased TNF-α concentration mayprovoke inflammatory cascade and induce the initiation of cytokine storm that may result in fatal pneumoniaand acute respiratory distress syndrome (ADRS). Hence, TNFα is assumed to be a promising drug targetagainst cytokine storm in COVID-۱۹ patients. In the present study, we focused on finding novel smallmolecules that can directly block TNF-α-hTNFR۱ (human TNF receptor ۱) interaction. In this regards, TNF-α-inhibiting capacity of natural carotenoids was investigated in terms of blocking TNF-α-hTNFR۱ interactionin COVID-۱۹ patients with the help of a combination of in silico approaches, based on virtual screening,molecular docking, and molecular dynamics (MD) simulation. A total of ۱۲۵ carotenoids were selected outof ۱۲۰۴ natural molecules, based on their pharmacokinetics properties and they all met Lipinski’s rule offive. Among them, Sorgomol, Strigol and Orobanchol had the most favorable ΔG with the best ADME(absorption, distribution, metabolism, excretion) properties, and were selected for MD simulation studies,which explored the complex stability and the impact of ligands on protein conformation. Our results showedthat Sorgomol formed the most hydrogen bonds, resulting in the highest binding energy with lowest RMSDand RMSF, which made it the most appropriate candidate as TNF-α inhibitor. In conclusion, the presentstudy could serve to expand possibilities to develop new therapeutic small molecules against TNF-α.

Keywords:

TNF-α , TNFR۱ , Carotenoid , COVID-۱۹ , Virtual Screening , Molecular Dynamics