In Silico Investigations of Possible Therapeutic Peptides as Drugs for Anti-Inflammatory Responses

Abstract

The chemokine called interleukin-8 (IL-8 or CXCL8) plays a central role in human immune response by binding and activating the receptor CXCR1 that belongs to the G-protein coupled receptor (GPCR) family. Upon binding of CXCL8, CXCR1 undergoes conformational change resulting in signal transduction.The purpose of this study was to determine the role of the fragments of the CXCL8 binding sites of CXCR1 as potential therapeutic targets for developing novel drugs against inflammatory diseases.Homology modeling studies were firstly performed to construct the three-dimensional structure of CXCR1 by taking the crystal structure of bovine rhodopsin (PDB code: 1U19) as the template with the sequence similarity up to 41.8 %. By the following molecular docking programs several potential peptides were selected and synthesized to validate the anti-inflammatory efficiency through flow cytometry analysis. The preferred complexes of CXCL8 binding CXCR1 from docking predictions were then embedded into POPC lipid bilayers for 50 ns MD simulation to investigate the binding interaction. Simulation results show that electrostatic interaction dominates the binding of CXCL8 and CXCR1, consistent with the previous experiments.Small peptide drugs are novel therapeutic candidates for inflammatory diseases. High-throughput, structure-based virtual screening combining MD simulations is an effective computer-based drug design method for discovering anti-inflammatory drug candidates.