A minimalistic 3D pharmacophore model for cyclopentapeptide CXCR4 antagonists

Because of its involvement in HIV entry, the chemokine receptor CXCR4 is an attractive target for antiretroviral drugs. Despite the large number of CXCR4 inhibitors studied, the 3D pharmacophore for binding to CXCR4 remains elusive, mainly as a result of conformational flexibility inherent in the identified ligands. In the present study, an exhaustive systematic exploration of the conformational space for a series of analogs of FC131, a cyclopentapeptide CXCR4 antagonist, has been performed. By comparing the resulting low-energy conformations using different sets of atoms, specific conformational features common only to the high/medium affinity compounds were identified. These features included the spatial arrangement of three pharmacophoric side chains as well as the orientation of a specific backbone amide bond. Together these features represent a minimalistic 3D pharmacophore model for binding of the cyclopentapeptide antagonists to CXCR4. The model enables rationalization of the experimental affinity data for this class of compounds as well as for the peptidomimetic KRH-1636.