Impact of the CXCR4 structure on docking-based virtual screening of HIV entry inhibitors

[Display omitted] ► CXCR4 crystal structures and a homology model are analyzed by retrospective docking. ► Structure 3OE6 shows the best EF at 1%, 5% and 10% of the screened database. ► Scaffold retrieval analysis for PDB 3OE6 recovers all chemotype families. ► A detailed analysis of the retrospective docking results using the CXCR4 homology model in Discovery Studio allows us to hypothesize the existence of multiple binding sub-sites in CXCR4 binding pocket. Herein we analyze in depth the receptor-based virtual screening (VS) performance of the five recent crystallized CXCR4 structures along with a CXCR4 rhodopsin-based homology model. All CXCR4 Protein Data Bank (PDB) structures are co-crystallized with a small organic antagonist except structure 3OE0, which is co-crystallized with a cyclic peptide analog. Evaluation of the CXCR4 models was done by retrospective docking-based VS using a test set of 248 known CXCR4 inhibitors from 4 different chemotype families and 4696 different presumed inactives. The performance of the docking protocol using the five different protein structures was assessed in terms of pose prediction and hits detection using 12 different docking scoring functions and a scoring function with rescoring. Results show that 3OE6 structure achieves the highest docking-based performance with an average area under the curve (aAUC) of 0.84 and an average enrichment factor (aEF) of 11.7 at 1% of decoys screened. CXCR4 rhodopsin-like homology model performs comparable to the crystallized structures in the 1% of database screened. Moreover, a detailed analysis of the retrospective docking results using the CXCR4 homology model in Discovery Studio allows us to hypothesize the existence of multiple binding sub-sites in CXCR4 binding pocket.