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Journal of Computer-Aided Molecular Design

, Volume 24, Issue 12, pp 1023–1033 | Cite as

Ligand-guided optimization of CXCR4 homology models for virtual screening using a multiple chemotype approach

  • Marco A. C. Neves
  • Sérgio Simões
  • M. Luisa Sá e Melo
Article

Abstract

CXCR4 is a G-protein coupled receptor for CXCL12 that plays an important role in human immunodeficiency virus infection, cancer growth and metastasization, immune cell trafficking and WHIM syndrome. In the absence of an X-ray crystal structure, theoretical modeling of the CXCR4 receptor remains an important tool for structure–function analysis and to guide the discovery of new antagonists with potential clinical use. In this study, the combination of experimental data and molecular modeling approaches allowed the development of optimized ligand-receptor models useful for elucidation of the molecular determinants of small molecule binding and functional antagonism. The ligand-guided homology modeling approach used in this study explicitly re-shaped the CXCR4 binding pocket in order to improve discrimination between known CXCR4 antagonists and random decoys. Refinement based on multiple test-sets with small compounds from single chemotypes provided the best early enrichment performance. These results provide an important tool for structure-based drug design and virtual ligand screening of new CXCR4 antagonists.

Keywords

CXCR4 CXCR4 antagonists Homology modeling Virtual screening Drug discovery 

Notes

Acknowledgments

M.A.C. Neves thanks Fundação para a Ciência e a Tecnologia (FCT), Portugal, for a Post Doctoral grant (SFRH/BPD/64216/2009) and the Fulbright Scholar Program for financial support. The authors are grateful to Dr. R. Abagyan, Dr. I. Kufareva, Dr. V. Katritch, Dr. P. Lam and Dr. M. Rueda for their stimulating discussions and support.

Supplementary material

10822_2010_9393_MOESM1_ESM.pdf (94 kb)
Online Resource 1. Full test-set of antagonists used for ligand-guilded optimization of CXCR4 homology models (PDF 94 kb)

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Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Marco A. C. Neves
    • 1
  • Sérgio Simões
    • 2
  • M. Luisa Sá e Melo
    • 1
  1. 1.Centro de Estudos Farmacêuticos, Laboratório de Química Farmacêutica, Faculdade de FarmáciaUniversidade de CoimbraCoimbraPortugal
  2. 2.Centro de Neurociências, Laboratório de Tecnologia Farmacêutica, Faculdade de FarmáciaUniversidade de CoimbraCoimbraPortugal

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