Journal of Computer-Aided Molecular Design

, Volume 27, Issue 7, pp 569–582 | Cite as

NMR-assisted computational studies of peptidomimetic inhibitors bound in the hydrophobic pocket of HIV-1 glycoprotein 41

  • Miriam Gochin
  • Landon R. Whitby
  • Aaron H. Phillips
  • Dale L. Boger


Due to the inherently flexible nature of a protein–protein interaction surface, it is difficult both to inhibit the association with a small molecule, and to predict how it might bind to the surface. In this study, we have examined small molecules that mediate the interaction between a WWI motif on the C-helix of HIV-1 glycoprotein-41 (gp41) and a deep hydrophobic pocket contained in the interior N-helical trimer. Association between these two components of gp41 leads to virus–cell and cell–cell fusion, which could be abrogated in the presence of an inhibitor that binds tightly in the pocket. We have studied a comprehensive combinatorial library of α-helical peptidomimetics, and found that compounds with strongly hydrophobic side chains had the highest affinity. Computational docking studies produced multiple possible binding modes due to the flexibility of both the binding site and the peptidomimetic compounds. We applied a transferred paramagnetic relaxation enhancement experiment to two selected members of the library, and showed that addition of a few experimental constraints enabled definitive identification of unique binding poses. Computational docking results were extremely sensitive to side chain conformations, and slight variations could preclude observation of the experimentally validated poses. Different receptor structures were required for docking simulations to sample the correct pose for the two compounds. The study demonstrated the sensitivity of predicted poses to receptor structure and indicated the importance of experimental verification when docking to a malleable protein–protein interaction surface.


HIV-1 glycoprotein-41 Molecular docking Paramagnetic relaxation NMR Protein–protein interaction Peptidomimetic inhibitors 



We gratefully acknowledge the financial support of the National Institutes of Health (NS059403, GM087998, MG), (CA078045, DLB). We thank E. Balogh and D. Wu for technical assistance in the collection of data for Fig. 1 and Table 1. Molecular graphics images were produced using the UCSF Chimera package from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIH P41 RR-01081). The authors also gratefully acknowledge use of the UC Berkeley Biomolecular NMR facility. The authors thank Dr. Eric Springman at Locus Pharmaceuticals (Ansaris) for providing the coordinates of 3p7k prior to publication.

Supplementary material

10822_2013_9662_MOESM1_ESM.docx (6.3 mb)
Supplementary material 1 (DOCX 6436 kb)


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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Miriam Gochin
    • 1
    • 2
  • Landon R. Whitby
    • 3
  • Aaron H. Phillips
    • 1
  • Dale L. Boger
    • 3
  1. 1.Department of Basic SciencesTouro University CaliforniaVallejoUSA
  2. 2.Department of Pharmaceutical ChemistryUniversity of CaliforniaSan FranciscoUSA
  3. 3.Department of ChemistryThe Scripps Research InstituteLa JollaUSA

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