Finding small chemical modulators capable of blocking 1 membrane-embedded CXCR4, a critical therapeutic target for renal fibrosis: a computational approach

Abstract Chronic kidney disease (CKD) often leads to renal fibrosis driven by CXCR4-mediated inflammation and tissue remodeling. This study aims to identify potential inhibitors of membrane-embedded CXCR4 isoform I through molecular docking and dynamics simulations. The AlphaFold-predicted human CXCR4 structure (AF-P61073-F1) was used for molecular dynamics simulations in GROMACS. Molecules with optimal ADME profiles and the top three lowest Glide scores were evaluated. Membrane simulations using RMSD, RMSF, SASA, Gyration, PCA, FEL, and per-residue decomposition analysis showed that compound 4993 interacted most stably with CXCR4. Additional simulations further confirmed 4993’s strong potential as a CXCR4 inhibitor. Furthermore, the membrane thickness, area per lipid, and Interdigitation analyses indicated that compound 4993 maintained favorable interactions contributing to membrane stability. These findings suggest that 4993 could play a significant role in modulating membrane properties, potentially contributing to its predicted effects, without implying confirmed therapeutic efficacy. Future studies should investigate the molecular mechanisms of CXCR4 interaction and their implications for drug development. The computational study concluded that membrane-embedded CXCR4 small-molecule inhibitor, such as compound 4993, has the potential to target CXCR4 and reduce kidney damage.