Abstract
NF-κB is a central regulator of immunity and inflammation. It is suggested that the inflammatory response mediated by SARS-CoV-2 is predominated by NF-κB activation. Thus, NF-κB inhibition is considered a potential therapeutic strategy for COVID-19. The aim of this study was to identify potential anti-inflammation lead molecules that target NF-κB using a quantitative structure-activity relationships (QSAR) model of currently used and investigated anti-inflammatory drugs as the basis for screening. We applied an integrated approach by starting with the inflammation-based QSAR model to screen three libraries containing more than 220,000 drug-like molecules for the purpose of finding potential drugs that target the NF-κB/IκBα p50/p65 (RelA) complex. We also used QSAR models to rule out molecules that were predicted to be toxic. Among screening libraries, 382 molecules were selected as potentially nontoxic and were analyzed further by short and long molecular dynamics (MD) simulations and free energy calculations. We have discovered five hit ligands with highly predicted anti-inflammation activity and nearly no predicted toxicities which had strongly favorable protein-ligand interactions and conformational stability at the binding pocket compared to a known NF-κB inhibitor (procyanidin B2). We propose these hit molecules as potential NF-κB inhibitors which can be further investigated in pre-clinical studies against SARS-CoV-2 and may be used as a scaffold for chemical optimization and drug development efforts.