Structure-based 3D-Pharmacophore modeling to discover novel interleukin 6 inhibitors: An in silico screening, molecular dynamics simulations and binding free energy calculations

Abstract

Interleukin 6 (IL-6) is a cytokine with various biological functions in immune regulation, hematopoiesis, and inflammation. Elevated IL-6 levels have been identified in several severe disorders such as sepsis, acute respiratory distress syndrome (ARDS), and most recently, COVID-19. The biological activity of IL-6 relies on interactions with its specific receptor, IL-6Rα, including the membrane-bound IL-6 receptor (mIL-6R) and the soluble IL-6 receptor (sIL-6R). Thus, inhibition of the interaction between these two proteins would be a potential treatment for IL-6 related diseases. To date, no orally available small-molecule drug has been approved. This study focuses on finding potential small molecules that can inhibit protein-protein interactions between IL-6 and its receptor IL-6Rα using its crystal structure (PDB ID: 5FUC). First, two pharmacophore models were constructed based on the interactions between key residues of IL-6 (Phe74, Phe78, Leu178, Arg179, Arg182) and IL-6Rα (Phe229, Tyr230, Glu277, Glu278, Phe279). A database of approximately 22 million compounds was screened using 3D-pharmacophore models, molecular docking models, and ADMET properties. By analyzing the interactive capability of successfully docked compounds with important amino acids, 12 potential ligands were selected for further analysis via molecular dynamics simulations. Based on the stability of the complexes, the high interactions rate of each ligand with the key residues of IL-6/IL-6Rα, and the low binding free energy calculation, two compounds ZINC83804241 and ZINC02997430, were identified as the most potential IL-6 inhibitor candidates. These results will pave the way for the design and optimization of more specific compounds to combat cytokine storm in severe coronavirus patients.

In Silico Molecular Docking and Dynamic Investigations of Bioactive Phytoconstituents from Fenugreek Seeds as a Potent Drug against DPP-IV Enzyme

“…The hydrogen bond interactions between protein and ligand across the entire MD simulations are crucial for the stability of a protein–ligand complex. Here, hydrogen bond analysis between protein and ligand was performed by using the “Hydrogen bond” plugin in VMD with a distance and angle cutoff of 3.5 Å and 120°, respectively. , In the present study, we considered the hydrogen bond occupancy to be greater than 20% for a significant contribution to protein–ligand interactions. All ligands acted as hydrogen bond donors and also as acceptors.…”

Identification of Diosmin and Flavin Adenine Dinucleotide as Repurposing Treatments for Monkeypox Virus: A Computational Study

“…During the simulations, the hydrogen bonds could form between the small-molecule ligands and the MPXV E8 protein residues. In this study, the hydrogen bonds were defined to occur if the bonding angle between the hydrogen donor (D) and acceptor (A) D-H⋯A larger than 120° with the distance between D and A not exceeding 3.5 Å [ 45 ]. The GROMACS prebuilt commands were used to calculate the root mean square deviation (RMSD), radius of gyration (Rg), and solvent-accessible surface area (SASA) of the protein backbone or the heavy atoms of the ligands for further evaluation.…”

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

“…In a study conducted by Tran Que-Huong et al, a pharmacophoric inhibitor was generated against IL-6Rα, called ZINC83804241. [7] The compound (ZINC83804241) was downloaded from the ZINC database and docked onto IL-6Rα using Autodock Vina to compare the affinity expressed by the inhibitor molecule suggested in this study and ZINC83804241.…”

“…In the study conducted by Tran Que-Huong et al, a pharmacophoric inhibitor was generated against IL-6Rα. [7] Their inhibitor of choice (ZINC83804241) was docked onto IL-6Rα using Autodock Vina. This inhibitor expressed a binding affinity of À 5.9 kcal/mol.…”

“…Scientists Que-Huong Tran et al have shown how blocking the interaction between IL-6 and IL-6Rα can be a viewed as a potential mode of treatment to prevent Covid-19. [7] Additionally, many studies have concentrated on targeting gp130 the central hub of the cytokine signaling pathway.…”