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Molecular Fields in Ligand Discovery

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Protein-Ligand Interactions

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1008))

Abstract

The discovery of novel biologically active small molecules is now a technologically and economically viable proposition for academic and small biotechnology laboratories wishing to build on their biological research into target proteins. Such small molecules may be useful reagents for further biological research or may form the basis for early-stage drug discovery. The availability of specialized virtual screening software to filter large molecular libraries into manageable numbers of compounds for biological assays is the driving force for finding novel ligands. The main focus of this chapter is the basis and use of molecular field methods to assess the interactions that may be made by small molecules. Molecular field based measures of capability and similarity of interaction may be used to discover novel ligands and expand ligand series for potential use as future therapies.

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References

  1. Nicholls A (2011) What do we know? Simple statistical techniques that help. In: Bajorath J (ed) Chemoinformatics and computational chemical biology. Springer Science, New York

    Google Scholar 

  2. Merz KM et al (2010) Drug design structure- and ligand-based approaches. CUP, Cambridge

    Book  Google Scholar 

  3. Leach AR (2001) Molecular modelling: principles and applications, 2nd edn. Longman, Edinburgh

    Google Scholar 

  4. Gasteiger J, Engel T (2004) Chemoinformatics: a textbook. Wiley, Wienheim

    Google Scholar 

  5. Young DC (2009) Computational drug design: a guide for computational and medicinal chemists. Wiley, New Jersey

    Book  Google Scholar 

  6. Rigby M et al (1986) The forces between molecules. OUP, Oxford

    Google Scholar 

  7. Stone AJ (2008) Intermolecular potentials. Science 321:787–789

    Article  PubMed  CAS  Google Scholar 

  8. Bissantz C, Kuhn B, Stahl M (2010) A medicinal chemist’s guide to molecular interactions. J Med Chem 53:5061–5084

    Article  PubMed  CAS  Google Scholar 

  9. Chan AW, Laskowski RA, Selwood DL (2010) Chemical fragments that hydrogen bond to Asp, Glu, Arg and His sidechains in protein binding sites. J Med Chem 53:3086–3094

    Article  PubMed  CAS  Google Scholar 

  10. Protein DataBank (PDB) at RCSB: http://www.rcsb.org/

  11. Williams MA, Ladbury JE (2003) Hydrogen bonds in protein–ligand complexes. In: Böhm HJ, Schneider G (eds) Protein–ligand interactions from molecular recognition to drug design. Wiley, Weinheim

    Google Scholar 

  12. Gilli G, Gilli P (2009) The nature of the hydrogen bond: outline of a comprehensive hydrogen bond theory. OUP, Oxford

    Book  Google Scholar 

  13. Labowski SJ (2006) Hydrogen bonding: new insights. Springer, Netherlands

    Google Scholar 

  14. Foloppe N (2005) Structure-based design of novel Chk1 inhibitors: Insights into hydrogen bonding and protein–ligand affinity. J Med Chem 48:4332–4345

    Article  PubMed  CAS  Google Scholar 

  15. Kubinyi H (2008) The changing landscape in drug discovery. In: Stroud RM, Finer-Moore J (eds) Computational and structural approaches to drug discovery. RSC, Cambridge

    Google Scholar 

  16. Parisini E et al (2011) Halogen bonding in halocarbon–protein complexes: a structural survey. Chem Soc Rev 40:2267–2278

    Article  PubMed  CAS  Google Scholar 

  17. Riley KE, Hobza P (2011) Strength and character of halogen bonds in protein–ligand complexes. Cryst Growth Des 11:4272–4278

    Article  CAS  Google Scholar 

  18. Hunter CA, Sanders JKM (1990) The nature of π–π Interactions. J Am Chem Soc 112:5525–5534

    Article  CAS  Google Scholar 

  19. Tsuzuki S (2005) Interactions with aromatic rings. Struc Bond 115:149–193

    Article  CAS  Google Scholar 

  20. Gooding M (2011) Exploring the interaction between siRNA and the SMoC biomolecule transporters: implications for small molecule-mediated delivery of siRNA. Chem Biol Drug Des 79:9–21

    Article  PubMed  Google Scholar 

  21. Lanzarotti E (2011) Aromatic–aromatic interactions in proteins: beyond the dimer. J Chem Inf Model 51:1623–1633

    Article  PubMed  CAS  Google Scholar 

  22. Barron LD, Hecht L, Wilson G (1997) The lubricant of life: a proposal that solvent water promotes extremely fast conformational fluctuations in mobile heteropolypeptide structure. Biochemistry 36:13143–13147

    Article  PubMed  CAS  Google Scholar 

  23. Setny P, Baron R, McCammon JA (2010) How can hydrophobic association be enthalpy driven? J Chem Theory Comput 6:2866–2871

    Article  PubMed  CAS  Google Scholar 

  24. Myslinski JM et al (2011) Protein–ligand interactions: thermodynamic effects associated with increasing nonpolar surface area. J Am Chem Soc 133:18518–18521

    Article  PubMed  CAS  Google Scholar 

  25. Hassan SA et al (2005) Computer simulation of protein–ligand interactions: challenges and applications. In: Nienhaus GU (ed) Protein–ligand Interactions. Humana, New Jersey

    Google Scholar 

  26. Schmidtke P et al (2011) Shielded hydrogen bonds as structural determinants of binding kinetics: application in drug design. J Am Chem Soc 133:18903–18910

    Article  PubMed  CAS  Google Scholar 

  27. Cavasotto CN, Phatak SS (2011) Docking methods for structure-based library design. In: Zhou JZ (ed) Chemical library design. Springer, New York

    Google Scholar 

  28. Irwin JJ, Shoichet BK (2005) ZINC – a free database of commercially available compounds for virtual screening. J Chem Inf Model 45:177–182

    Article  PubMed  CAS  Google Scholar 

  29. Li R et al (2011) Development of a method to consistently quantify the structural distance between scaffolds and to assess scaffold hopping potential. J Chem Inf Model 57:2507–2514

    Article  Google Scholar 

  30. Wermuth CG (2008) The practice of medicinal chemistry. Academic, London

    Google Scholar 

  31. Low CMR (2005) Scaffold hopping with molecular field points: identification of a cholecystokinin-2 (CCK2) receptor pharmacophore and its use in the design of a prototypical series of pyrrole- and imidazole-based CCK2 antagonists. J Med Chem 48:6790–6802

    Article  PubMed  CAS  Google Scholar 

  32. Warwicker J (1994) Improved continuum electrostatic modelling in proteins, with comparison to experiment. J Mol Biol 236:887–903

    Article  PubMed  CAS  Google Scholar 

  33. Apaya RP (1995) The matching of electrostatic extrema: a useful method in drug design? A study of phosphodiesterase III inhibitors. J Comput Aided Mol Des 9:33–43

    Article  PubMed  CAS  Google Scholar 

  34. Bruno IJ et al (1997) Isostar: a library of information about non-bonded interactions. J Comput Aided Mol Des 11:525–537, http://www.ccdc.cam.ac.uk/products/csd_system/isostar/

    Article  PubMed  CAS  Google Scholar 

  35. Cresset software http://www.cresset-group.com

  36. Vinter JG (1994) Extended electron distributions applied to molecular mechanics of intermolecular interactions. J Comput Aided Mol Des 8:653–668

    Article  PubMed  CAS  Google Scholar 

  37. Cheeseright T et al (2006) Molecular field extrema as descriptors of biological activity: definition and validation. J Chem Inf Model 46:665–676

    Article  PubMed  CAS  Google Scholar 

  38. Goodford PJ (1985) A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. J Med Chem 28:849–857

    Article  PubMed  CAS  Google Scholar 

  39. OpenEye http://www.eyesopen.com/

  40. MOE (Molecular Operating Environment) http://www.chemcomp.com/software.htm

  41. GOLD http://www.ccdc.cam.ac.uk/products/life_sciences/gold/

  42. Gane PJ, Chan E, Selwood D. ChemiBank http://www.ucl.ac.uk/chemibank

  43. John Hopkins clinical collection http://htc.wustl.edu/library/JHCCL.html

  44. Mol2 format http://tripos.com/tripos_resources/fileroot/pdfs/mol2_format.pdf

  45. Rishton GM (2003) Non-leadlikeness and leadlikeness in biochemical screening. DDT 8:86–96

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

OpenEye for free access to their full suite of programs, MOE and GOLD for their generous academic pricing, Cresset for their free teaching licenses and support. Andy Vinter and Martin Slater for their excellent advice.

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Authors and Affiliations

  1. Medicinal Chemistry, Wolfson Institute for Biomedical Research, University College London, London, UK

    Paul J. Gane & A. W. Edith Chan

Authors
  1. Paul J. Gane
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  2. A. W. Edith Chan
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Editor information

Editors and Affiliations

  1. Birbeck, University of London, ISMB Biophysics Centre, Institute of Str, Malet Street, London, WC1E 7HX, United Kingdom

    Mark A. Williams

  2. Birkbeck, University of London, School of Crystallography, ISMB Biophysics Centre, Institute of Str, Malet Street, London, WC1E 7HX, United Kingdom

    Tina Daviter

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Gane, P.J., Chan, A.W.E. (2013). Molecular Fields in Ligand Discovery. In: Williams, M., Daviter, T. (eds) Protein-Ligand Interactions. Methods in Molecular Biology, vol 1008. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-398-5_18

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  • DOI: https://doi.org/10.1007/978-1-62703-398-5_18

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  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-62703-397-8

  • Online ISBN: 978-1-62703-398-5

  • eBook Packages: Springer Protocols

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