Conformational Plasticity of Interleukin-8 Mediates Its Dynamic Molecular Interaction with Potent Inhibitor Suramin.

Structural plasticity of proteins is a crucial and regulatory factor that mediates protein-protein/ligand interactions. It signifies the specificity of protein interactions and is one of the most essential rate-limiting steps in the field of drug discovery. Chemokines are small cationic inflammatory proteins, well-known for their plasticity-governed promiscuous features. They specifically interact with chemokine receptors (GPCRs) and glycosaminoglycans (GAGs). Particularly, interleukin-8 (IL8/CXCL8) is a proinflammatory chemokine associated with leukocyte/neutrophil trafficking via IL8-GPCR (CXCR1/CXCR2) and GAG signaling axis. It is involved in various acute and chronic diseases and is a critical target for the development of anti-inflammatory therapeutics. Studies of synthetic molecules such as sulfonamides have shown their potency to mimic GAG interactions for viral proteins. Hence, the current study investigates a sulfonamide derivative, suramin, as a potential interactor of IL8 utilizing a combination of computational and biophysical techniques. The binding energetics revealed that suramin interacts with IL8 with a dissociation constant of 3.02 ± 0.4 μM. Structural data established the overlapping binding site of suramin on IL8 in the receptor/GAG binding pocket. Further, structural and biophysical analyses indicate that the stability, dynamics, and conformity of IL8-suramin interactions are influenced by structural plasticity and heterogeneity. Overall, this study elucidated the role of protein plasticity in protein-ligand/inhibitor interactions, and the data obtained propose the potential application of suramin as a potential inhibitor, which could be useful in targeting chemokine-GAG/receptor interactions in regulating IL8-mediated inflammatory conditions.