Molecular Dynamics Simulation Studies reveal NF-kappa B as a strong therapeutic drug target for COVID19

Abstract

COVID19 caused due to SARS-CoV2, is rampant world wide and human beings with previous history of other major ailments are increasingly at risk of mortality due to this disease in a predetermined manner. Countries have developed vaccines claiming to counter the SARS-CoV2 virus to a great extent. However, convincing evidences are lacking in this regard as mortality post-vaccination is not uncommon, though exact reason of the morbidity is unknown yet. Our current work primarily focuses on molecular dynamics simulation (MDS) targeting NF-kappa B (NF-κB), the well-known human transcription factor that controls innate and adaptive immunity, with an aim to understand its mechanism of action under COVID19 virus load in humans. To understand this, NF-κB was made to interact with spike protein of SARS-CoV2 in an in silico experimental design employing Molecular Dynamics Simulation (MDS) studies. Some interesting findings were made revealing the site of NF-κB at which spike protein of SARS-CoV2 interacts. We attempted to subject some known drugs to be screened based on their docking studies with nuclear factor kappa B (NF-κB) to MDS studies. MDS Software Schrodinger generated more than 2000 complexes from these compounds and structure exportation was hence not possible. Using the SMILE IDs of 243 ligands, we generated a total of 411 confirmers employing the ligand preparation wizard. These were docked at the active site using the Glide program. A drug named Sulindac sodium (Molecular Formula C20H16FO3S) was found having ability to target NF-κB and can be repurposed for controlling SARS-CoV2 based on the positive results obtained during MDS analysis. This drug showed potency to block the spike protein’s interaction with NF-κB by bringing about a conformational change in the latter. It is hypothesized presently that NF-κB activation that leads to migration of this molecule to nucleus for gene transcription and immunity inhibition, is triggered either directly by binding of spike protein to NF-κB or spike protein’s interaction with some pathway kinase that phosphorylates IκBs, another molecule essential to get released from the NF-κB-IκB complex, to set NF-κB free to get translocated to nucleus for action. Arguably, NF-κB inaction is desired to allow normal immunity to become functional and can possibly be retained using our repurposed drug-based interaction. This work provides a significant lead in the knowledge on drug development for tackling SARS-CoV2 and its various mutant forms by blocking the functioning of the virus in a NF-κB-dependent manner in host tissues and opens up new vistas in controlling critical state SARS-CoV2 disease.