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.
['Oum|Yoon Hyeun|YH|', 'Kell|Steven A|SA|', 'Yoon|Younghyoun|Y|', 'Liang|Zhongxing|Z|', 'Burger|Pieter|P|', 'Shim|Hyunsuk|H|']
D000818:Animals D000893:Anti-Inflammatory Agents D045744:Cell Line, Tumor D015195:Drug Design D006801:Humans D007249:Inflammation D051379:Mice D062105:Molecular Docking Simulation D056004:Molecular Dynamics Simulation D015394:Molecular Structure D010880:Piperidines D011485:Protein Binding D019718:Receptors, CXCR4 D013329:Structure-Activity Relationship
C-X-C chemokine receptor type 4 (CXCR4) Molecular dynamics Chemokine modulator Ligand shape similarity Molecular docking Structure-based drug design