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 (IC 50 = 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. Image 1 • 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. [ABSTRACT FROM AUTHOR]