Transcription factor NF-κB as target for SARS-CoV-2 drug discovery efforts using inflammation-based QSAR screening model

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 relationship (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. Only 382 molecules were selected as potentially nontoxic and were analyzed further by short and long molecular dynamic (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.

Identifying Drug-Induced Liver Injury Associated With Inflammation-Drug and Drug-Drug Interactions in Pharmacologic Treatments for COVID-19 by Bioinformatics and System Biology Analyses: The Role of Pregnane X Receptor

“…Whereas, the augmented system is a double-edged sword for DILI in COVID-19 patients because it needs to convert parent drug into toxic reactive intermediates, e.g., ritonavir, to facilitate the detoxification of exogenous compounds. In addition, PXR played pleiotropic effects on DILI: this xenosensor could be inhibited by significant liver inflammatory response, attributing to CRS of COVID-19, via the crosstalk with NF-κB ( Zordoky and El-Kadi, 2009 ; Kanan et al, 2021 ). The p65 subunit, increased by IL-6 and other released cytokines, interacted with the PXR partner RXRα to inhibit hepatic metabolism system ( Moreau et al, 2008 ).…”

A short review on recent developments in the computational techniques (2021) to mitigate SARS-CoV-19 disease

“…ADMET and ADME (Absorption, Distribution, Metabolism, Excretion) properties of the 8 proposed molecules were calculated using pkCSM [68] and SwissADME [69] (ADME =Adsorption, Distribution, Metabolism, Excretion ) online tools. The carboxamides sulfonamide scaffold showed good pharmacokinetics with moderate absorption, satisfactory metabolic transformation and no toxicity as far as the inhibitory properties against SARS-CoV-2 is concerned.…”

NF‐κB signaling in inflammation and cancer

“… 262 SARS‐CoV‐2 mediates inflammation by activating NF‐κB, so the development of drugs that inhibit NF‐κB is currently considered to be one of the potential treatment strategies for COVID‐19. 272 A clinical trial used the BTK inhibitor acalabrutinib to treat severe COVID‐19 patients, and the result showed that C‐reactive protein and IL‐6 levels were reduced, and patients' oxygen saturation improved. 273 Another study used diosmectite in the SARS‐CoV‐2 model, as diosmectite can bind to SARS‐CoV‐2 components and inhibit NF‐κB activation and CXCL10 secretion and inhibit downstream inflammation, indicating the potential value of diosmectite for COVID‐19‐related diarrhea.…”