Skip to main content
SpringerLink
Log in

Structure-Based Functional Design of Drugs: From Target to Lead Compound

  • Protocol
  • First Online:
Book cover Molecular Profiling

Part of the book series: Methods in Molecular Biology ((MIMB,volume 823))

Abstract

Proteomic and genomic discoveries have identified vast numbers of new drug targets for investigation. In the quest to discover drugs that modulate the function of these targets, identification of small-molecule drug leads is one of the earliest steps. Structure-based drug design has emerged as a valuable, inexpensive, and rapid computational resource that identifies lead compounds that are complementary to the structure of the target. Leads identified through this process are biologically evaluated and “hit compounds” with affinity and activity are further optimized. This chapter introduces the process of structure-based drug design, including preparation of the ligand database, preparation of the target structure, docking and scoring, and evaluation.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Anderson, A. C. (2003) The process of structure-based drug design. Chem Biol 10, 787–97.

    Google Scholar 

  2. McInnes, C. (2007) Virtual screening strategies in drug discovery. Curr Opin Chem Biol 11, 494–502.

    Google Scholar 

  3. Moitessier, N., Englebienne, P., Lee, D., Lawandi, J., Corbeil, C. R. (2008) Towards the development of universal, fast and highly accurate docking/scoring methods: a long way to go. Br J Pharmacol 153 Suppl 1, S7-26.

    Google Scholar 

  4. Cummings, M. D., DesJarlais, R. L., Gibbs, A. C., Mohan, V., Jaeger, E. P. (2005) Comparison of automated docking programs as virtual screening tools. J Med Chem 48, 962–76.

    Google Scholar 

  5. Warren, G. L., Andrews, C. W., Capelli, A. M., Clarke, B., LaLonde, J., Lambert, M. H. et al. (2006) A critical assessment of docking programs and scoring functions. J Med Chem 49, 5912–31.

    Google Scholar 

  6. Wang, R., Lu, Y., Wang, S. (2003) Comparative evaluation of 11 scoring functions for molecular docking. J Med Chem 46, 2287–303.

    Google Scholar 

  7. Irwin, J. J., Shoichet, B. K. (2005) ZINC--a free database of commercially available compounds for virtual screening. J Chem Inf Model 45, 177–82.

    Google Scholar 

  8. Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H. et al. (2000) The Protein Data Bank. Nucleic Acids Res 28, 235–42.

    Google Scholar 

  9. Lipinski, C. A., Lombardo, F., Dominy, B. W., Feeney, P. J. (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46, 3–26.

    Google Scholar 

  10. Veber, D. F., Johnson, S. R., Cheng, H. Y., Smith, B. R., Ward, K. W., Kopple, K. D. (2002) Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 45, 2615–23.

    Google Scholar 

  11. Huang, S. Y., Grinter, S. Z., Zou, X. (2010) Scoring functions and their evaluation methods for protein-ligand docking: recent advances and future directions. Phys Chem Chem Phys 12, 12899–908.

    Google Scholar 

  12. Shoichet, B. K., Leach, A. R., Kuntz, I. D. (1999) Ligand solvation in molecular docking. Proteins 34, 4–16.

    Google Scholar 

  13. Liu, H.-Y., Kuntz, I. D., Zou, X. (2004) Pairwise GB/SA scoring function for structure-based drug design. J Phys Chem B 108, 5453–5462.

    Google Scholar 

  14. Hattotuwagama, C. K., Davies, M. N., Flower, D. R. (2006) Receptor-ligand binding sites and virtual screening. Curr Med Chem 13, 1283–304.

    Google Scholar 

  15. Plount Price, M. L., Jorgensen, W. L. (2000) Analysis of Binding Affinities for Celecoxib Analogues with COX-1 and COX-2 from Combined Docking and Monte Carlo Simulations and Insight into the COX-2/COX-1 Selectivity. J Am Chem Soc 122, 9455–9466.

    Google Scholar 

  16. Bolstad, E. S., Anderson, A. C. (2008) In pursuit of virtual lead optimization: the role of the receptor structure and ensembles in accurate docking. Proteins 73, 566–80.

    Google Scholar 

  17. B-Rao, C., Subramanian, J., Sharma, S. D. (2009) Managing protein flexibility in docking and its applications. Drug Discov Today 14, 394–400.

    Google Scholar 

  18. Paulsen, J. L., Anderson, A. C. (2009) Scoring ensembles of docked protein:ligand interactions for virtual lead optimization. J Chem Inf Model 49, 2813–9.

    Google Scholar 

  19. Totrov, M., Abagyan, R. (2008) Flexible ligand docking to multiple receptor conformations: a practical alternative. Curr Opin Struct Biol 18, 178–84.

    Google Scholar 

  20. McMartin, C., Bohacek, R. S. (1997) QXP: powerful, rapid computer algorithms for structure-based drug design. J Comput Aided Mol Des 11, 333–44.

    Google Scholar 

  21. Schnecke, V., Swanson, C. A., Getzoff, E. D., Tainer, J. A., Kuhn, L. A. (1998) Screening a peptidyl database for potential ligands to proteins with side-chain flexibility. Proteins 33, 74–87.

    Google Scholar 

  22. Jones, G., Willett, P., Glen, R. C., Leach, A. R., Taylor, R. (1997) Development and validation of a genetic algorithm for flexible docking. J Mol Biol 267, 727–48.

    Google Scholar 

  23. Knegtel, R. M., Kuntz, I. D., Oshiro, C. M. (1997) Molecular docking to ensembles of protein structures. J Mol Biol 266, 424–40.

    Google Scholar 

  24. Moustakas, D. T., Lang, P. T., Pegg, S., Pettersen, E., Kuntz, I. D., Brooijmans, N. et al. (2006) Development and validation of a modular, extensible docking program: DOCK 5. J Comput Aided Mol Des 20, 601–19.

    Google Scholar 

  25. Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S. et al. (2009) AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 30, 2785–91.

    Google Scholar 

  26. Friesner, R. A., Banks, J. L., Murphy, R. B., Halgren, T. A., Klicic, J. J., Mainz, D. T. et al. (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47, 1739–49.

    Google Scholar 

  27. Rarey, M., Kramer, B., Lengauer, T., Klebe, G. (1996) A fast flexible docking method using an incremental construction algorithm. J Mol Biol 261, 470–89.

    Google Scholar 

  28. Jain, A. N. (2003) Surflex: fully automatic flexible molecular docking using a molecular similarity-based search engine. J Med Chem 46, 499–511.

    Google Scholar 

  29. Boehm, H.-J. (1992) The computer program LUDI: A new method for the de novo design of enzyme inhibitors. 6, in Journal of Computer-Aided Molecular Design. Springer Netherlands, 61–78.

    Google Scholar 

  30. Goodford, P. J. (1985) A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. J Med Chem 28, 849–57.

    Google Scholar 

Download references

Acknowledgments

The author thanks Dr. Erin Bolstad for her critical review and ­comments. This work was supported by NIGMS (GM 067542).

Author information

Authors and Affiliations

  1. School of Pharmacy, University of Connecticut, Storrs, CT, USA

    Amy C. Anderson

Authors
  1. Amy C. Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amy C. Anderson .

Editor information

Editors and Affiliations

  1. Center for Applied Proteomics and, George Mason University, University Blvd. 10900, Manassas, 20110, Virginia, USA

    Virginia Espina

  2. Center for Applied Proteomics &, George Mason University, University Blvd. 10900, Manassas, 20110, Virginia, USA

    Lance A. Liotta

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Anderson, A.C. (2012). Structure-Based Functional Design of Drugs: From Target to Lead Compound. In: Espina, V., Liotta, L. (eds) Molecular Profiling. Methods in Molecular Biology, vol 823. Humana Press. https://doi.org/10.1007/978-1-60327-216-2_23

Download citation

  • DOI: https://doi.org/10.1007/978-1-60327-216-2_23

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60327-215-5

  • Online ISBN: 978-1-60327-216-2

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation