Molecular Design of Novel Inhibitor by Targeting IL‐6Rα using Combined Pharmacophore and Experimentally Verified Plant Products with Scaffold‐Hopping Techniques: A Dual Therapeutic Strategy for COVID‐19 and Cancer

Abstract

AbstractThe IL‐6/IL‐6R/gp130 complex serves as a significant indicator of cytokine release syndrome in COVID‐19 and chronic inflammation, increasing the risk of cancer. Therefore, we identified IL‐6Rα as a potential target to block gp130 interaction. Notably, there has been no reception of approval for an orally available drug to serve this purpose, to date. In this study, we targeted IL‐6Rα to inhibit IL‐6Rα/gp130 interaction. The selection of the lead candidate L821 involved the amalgamation of three drug discovery approaches. This library was screened employing tertiary structure‐based pharmacophore models followed by molecular docking models, scaffold‐hopping, MM/PBSA as well as MM/GBSA analysis, and assessments of pKi and ADMET properties. After evaluating the binding interactions with key amino acids, 15 potential ligands were chosen, with the top ligand undergoing further investigation by means of molecular dynamics simulations. Considering the stability of the complexes, the strong interactions observed between ligand and residues of IL‐6Rα/gp130, and the favorable binding free energy calculations, L821 emerged as the prime candidate for inhibiting IL‐6Rα. Notably, L821 exhibited a docking‐based binding affinity of −9.5 kcal/mol. Our study presents L821 as a promising inhibitor for future in vitro analysis, potentially combatting SARS‐CoV‐2‐related cytokine storms and serving as an oncogenic drug therapy.