A minimalistic 3D pharmacophore model for cyclopentapeptide CXCR4 antagonists

Abstract

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.

Progress Toward Rationally Designed Small-Molecule Peptide and Peptidomimetic CXCR4 Antagonists

“…Based on an extensive exploration of the conformational space for a series of reported cyclopentapeptide CXCR4 antagonists, Våbenø et al have proposed a minimalistic 3D pharmacophore model for this compound class [101]. The identified features included the spatial arrangement of the pharmacophoric side chains as well as the optimal conformation of the cyclopentapeptide backbone, which was consistent with the experimental solution structure for FC131 [49].…”

“…No further investigation into this scaffold has been published to date. considered as a tripeptidomimetic [101]. In the original study, KRH--1636 was found to be duodenally absorbable and was considered as a promising lead.…”

Molecular Pharmacology of CXCR4 Inhibition

“…In an extensive study from 2006, 11 derivatives of FC131, which were believed to share a common binding mode, were docked to a threedimensional model of the transmembrane region of CXCR4 [ 38 ] . The authors had previously published a minimalistic 3D pharmacophore model for cyclopentapeptides suggesting the spatial arrangement of the domains required for CXCR4 binding [ 39 ] , and the ligands were docked according to this model to further elucidate the atomic details of the CXCR4 interaction.…”

Design, synthesis, and biological evaluation of scaffold-based tripeptidomimetic antagonists for CXC chemokine receptor 4 (CXCR4)

“…This material was prepared by guanidinylation of glycine methyl ester hydrochloride (18) using N,N-di-Boc-1H-pyrazole-1-carboxamidine followed by hydrolysis of the methyl ester of the resulting 19…”