2. Academic Validation
  3. Tetrahydroisoquinoline CXCR4 Antagonists Adopt a Hybrid Binding Mode within the Peptide Subpocket of the CXCR4 Receptor

Tetrahydroisoquinoline CXCR4 Antagonists Adopt a Hybrid Binding Mode within the Peptide Subpocket of the CXCR4 Receptor

  • ACS Med Chem Lett. 2018 Nov 30;10(1):67-73. doi: 10.1021/acsmedchemlett.8b00441.
Brooke M Katzman 1,  Bryan D Cox 1,  Anthony R Prosser 1,  Ana A Alcaraz 1,  Brigitte Murat 2,  Madeleine Héroux 2,  Andrew Tebben 3,  Yong Zhang 3,  Gretchen M Schroeder 3,  James P Snyder 1,  Lawrence J Wilson 1,  Dennis C Liotta 1
Affiliations

Affiliations

  • 1 Department of Chemistry, Emory University, 1521 Dickey Drive, Atlanta, Georgia 30322, United States.
  • 2 Medicinal Chemistry platform, Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Québec H3C 3J7, Canada.
  • 3 Bristol-Myers Squibb R&D, US Route 206 and Province Line Road, Princeton, New Jersey 08543-4000, United States.
PMID: 30655949 DOI: 10.1021/acsmedchemlett.8b00441
Abstract

The rationale for the structural and mechanistic basis of a tetrahydroisoquinoline (THIQ) based series of CXCR4 antagonists is presented. Using the previously reported crystal structures which reveal two distinct binding sites of CXCR4 defined as the small molecule (IT1t or minor) binding pocket and peptide (CVX15 or major) binding pocket, we hypothesized our THIQ small molecule series could bind like either molecule in these respective receptor configurations (IT1t versus CVX15 based poses). To this end, a thorough investigation was performed through a combination of receptor mutation studies, medicinal chemistry, biological testing, conformational analysis, and flexible docking. Our findings showed that the CVX15 peptide-based CXCR4 receptor complexes (red pose) were consistently favored over the small molecule IT1t based CXCR4 receptor configurations (blue pose) to correctly explain the computational and mutational studies as well as key structural components of activity for these small molecules.

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