Discovery of novel aminopiperidinyl amide CXCR4 modulators through virtual screening and rational drug design

The C-X-C chemokine receptor type 4 (CXCR4) is a potential therapeutic target for HIV infection, metastatic cancer, and inflammatory autoimmune diseases. In this study, we screened the ZINC chemical database for novel CXCR4 modulators through a series of in silico guided processes. After evaluating the screened compounds for their binding affinities to CXCR4 and inhibitory activities against the chemoattractant CXCL12, we identified a hit compound (ZINC 72372983) showing 100 nM affinity and 69% chemotaxis inhibition at the same concentration (100 nM). To increase the potency of our hit compound, we explored the protein-ligand interactions at an atomic level using molecular dynamics simulation which enabled us to design and synthesize a novel compound (Z7R) with nanomolar affinity (IC50 = 1.25 nM) and improved chemotaxis inhibition (78.5%). Z7R displays promising anti-inflammatory activity (50%) in a mouse edema model by blocking CXCR4-expressed leukocytes, being supported by our immunohistochemistry study. [Display omitted] •New CXCR4 ligands were identified by in silico screenings and in vitro assays.•A novel compound was rationally designed from the hit compound using MD simulation.•Z7R displayed nanomolar binding affinity (1 nM) and inhibited 79% of chemotaxis.•Z7R demonstrated 50% anti-inflammatory activity in a mouse edema model.