Highly specific and sensitive pharmacophore model for identifying CXCR4 antagonists. Comparison with docking and shape-matching virtual screening performance.

HIV infection is initiated by fusion of the virus with the target cell through binding of the viral gp120 protein with the CD4 cell surface receptor protein and the CXCR4 or CCR5 coreceptors. There is currently considerable interest in developing novel ligands that can modulate the conformations of these coreceptors and, hence, ultimately block virus-cell fusion. Herein, we present a highly specific and sensitive pharmacophore model for identifying CXCR4 antagonists that could potentially serve as HIV entry inhibitors. Its performance was compared with docking and shape-matching virtual screening approaches using 3OE6 CXCR4 crystal structure and high-affinity ligands as query molecules, respectively. The performance of these methods was compared by virtually screening a library assembled by us, consisting of 228 high affinity known CXCR4 inhibitors from 20 different chemotype families and 4696 similar presumed inactive molecules. The area under the ROC plot (AUC), enrichment factors, and diversity of the resulting virtual hit lists was analyzed. Results show that our pharmacophore model achieves the highest VS performance among all the docking and shape-based scoring functions used. Its high selectivity and sensitivity makes our pharmacophore a very good filter for identifying CXCR4 antagonists.