Identifying modulators of CXC receptors 3 and 4 with tailored selectivity using multi-target docking

Area of Science:

• Molecular biology
• Pharmacology
• Computational chemistry

Background:

• Chemokine receptors, specifically C-X-C chemokine receptor type 3 (CXCR3) and C-X-C chemokine receptor type 4 (CXCR4), are implicated in severe diseases including cancer, multiple sclerosis, and HIV.
• Targeting both CXCR3 and CXCR4 simultaneously offers potential for polypharmacological drug treatments, but dual binders have not been previously identified.

Purpose of the Study:

• To identify novel dual modulators targeting both CXCR3 and CXCR4.
• To predict compounds with selective binding profiles for either CXCR3 or CXCR4 using computational methods.
• To validate the efficacy of computational predictions through experimental assays.

Main Methods:

• Large-scale molecular docking simulations were performed on the structure of CXCR4 and a homology model of CXCR3.
• Predicted ligands were screened and validated using signaling and biochemical assays.
• Computational predictions were assessed for accuracy in identifying dual binders and selective compounds.

Main Results:

• Over 50% of the computationally predicted ligands demonstrated correct binding profiles for each category (dual or selective).
• Identified ligands exhibited excellent binding efficiencies.
• Novel CXCR3-CXCR4 dual modulators were discovered, validating the computational approach.

Conclusions:

• Molecular docking is an effective tool for identifying ligands with specific binding profiles for G protein-coupled receptors (GPCRs), even when utilizing homology models.
• The identified novel dual modulators for CXCR3 and CXCR4 may advance the understanding of polypharmacological inhibition mechanisms for these receptors.