Progress in structure-based drug development targeting chemokine receptors

Abstract

As a critical subfamily of G protein-coupled receptors (GPCRs), chemokine receptors (CCRs) play pivotal regulatory roles in immune cell migration, inflammatory modulation, tissue regeneration, and tumor microenvironment (TME) remodeling. By specifically recognizing chemokine ligands, CCRs orchestrate immune cell trafficking and tissue positioning, with functional dysregulation implicated in infectious diseases, autoimmune disorders, neurodegenerative pathologies, and cancer. These receptors thus represent promising therapeutic targets. Recent breakthroughs in cryo-electron microscopy (cryo-EM) and computational chemistry have enabled high-resolution structural analysis and dynamic conformational modeling of CCRs, establishing a robust foundation for structure-based drug design (SBDD). This review synthesizes current advances in CCR biology, structural mechanisms, disease involvement, and targeted drug development, providing theoretical insights and technical frameworks for future research.

Keywords: CCRs; GPCR; cryo-EM; drug discovery; structure-based drug design (SBDD).

FIGURE 1

Schematic diagram of structure-based drug development targeting chemokine receptors. This figure illustrates the transmembrane structural features of chemokine receptors, the activation of downstream G protein–and β-arrestin–mediated signaling pathways upon ligand binding, and the functional dysregulation of these receptors in diseases such as inflammation, tumor immunity, and viral infection. It also highlights candidate small-molecule drugs designed based on receptor structural features, providing an integrated framework from receptor structure to function and therapeutic targeting.

FIGURE 2

Chemokine Receptor Interaction Network. Left: Chemokine receptors include four families—CCR, CXCR, XCR, and CX3CR—which form a complex interaction network with chemokines. A single chemokine receptor can be activated by multiple chemokines, and a single chemokine can activate multiple chemokine receptors. Blue: CCR; peach: CXCR; gray: XCR; purple: CX3CR.Right: Atypical chemokine receptor family, mainly including ACKR1–ACKR5, can also recognize multiple chemokines. Magenta: ACKR.

FIGURE 3

Schematic Illustration of GPCR Activation. Upon ligand binding, the receptor undergoes a conformational change into a pre-activated state, coupled with the G protein heterotrimer. The exchange of GDP for GTP on the G protein α subunit triggers G protein dissociation, leading to the activation of various G protein-mediated signaling pathways, including Gs, Gi, Gq, and G12/13 pathways.

FIGURE 4

Schematic Diagram of the Chemokine “Two-Site Model”. (A) The recognition of chemokines by the four chemokine receptor families—CCR, CXCR, CX3CR, and XCR—follows the “two-site model.” CRS1 primarily involves interactions between the globular core region of the chemokine and the N-terminal domain (N-term) and extracellular loops (ECLs) of the receptor. CRS1.5 plays a crucial bridging role in ligand recognition and receptor activation, ensuring the correct insertion of the chemokine N-terminus into the transmembrane binding pocket. CRS2 is mainly responsible for the insertion of the chemokine N-terminus into the receptor’s transmembrane domain, forming a structural binding pocket. (CXCL12-CXCR4 complex PDB:8K3Z; CCL2-CCR2 complex PDB:7XA3; XCL1-CXR1 complex PDB:9AST; CX3CL1-CX3CR1 complex PDB:7XBX). (B) Structural overview of CCR2 in complex with its endogenous ligand CCL2. Left: The orthosteric chemokine-binding pocket of CCR2 and the overall architecture of the CCR2–CCL2 complex. Right: Detailed interactions between CCR2 and CCL2 at the chemokine recognition sites CRS1 and CRS2.

FIGURE 5

Research Workflow for Structure-Based Design of Small-Molecule Drugs Targeting GPCRs. The experimental workflow mainly consists of four parts: expression and purification of the target GPCR protein, cryo-EM sample preparation and structure determination, structure-based small-molecule screening, and functional validation.

FIGURE 6

Maraviroc-binding pocket of CCR5. (A) Key residues involved in the binding of CCR5 to maraviroc. Maraviroc (orange) and interacting receptor residues (blue) are shown as sticks. (B) Schematic representation of the interactions between CCR5 and maraviroc. Mutations reported to be critical for maraviroc binding are highlighted in red. Maraviroc–CCR5 complex PDB: 4MBS.