Scaffold hopping - Mid year review 2007

"The 'fitness-landscape' is the relation of a molecular descriptor (the landscape) with a desired property (the fitness), which can be e.g. the binding affinity, selectivity or metabolic stability. An ideal 'fitness-landscape' would be smooth with respect to the neighborhood of molecules. In such a 'fitness-landscape' similar molecules would exhibit similar properties. 'Fitness-landscapes' representing the QSAR of molecules in drug discovery projects are believed to be jagged." [msl04] and [ren06]

Rajarshi has given a short review about 'scaffold hopping' (SH). An extensive review about SH can be found in the work of S. Renner [ren06,ssr06]. He earned his doctorate in G. Schneider's group, which coined the term 'scaffold hopping' (SH).

"Scaffold hopping is one of the most challenging goals in virtual screening. Ideal virtual screening methods would not only find a maximum number but also a maximum diverse set of active compounds from a given chemical subspace. There are several reasons for seeking a set of diverse structures. Diverse structures offer the medicinal chemist a choice in terms of chemical accessibility and prospects for lead optimization. Multiple leads ('backup' leads) lower the chance of drug development attrition in case of undesirable ADMET properties. Furthermore, the creation of intellectual property is facilitated." [ren06]

SH describes the ability of a similarity metric to identify bioactive compounds belonging to novel structural classes for particular biological targets. The key is here identifying novel and diverse chemotypes, which cover hopefully a patent-free space. In other words is this not a pure similarity searching in biological space, but also a diversity search in chemical space. More details about similarity searches can be found in two recent reviews about similarity metrics [ga06] and molecule mining methods.

In drug design multiple methods of SH for finding new leads and drugs are possible

• scaffold or substructure based for adenosine receptors [nce05] and 52 diverse active molecules [sam07]
• pharmacophore based for phosphodiesterase inhibitors [ykf06]
  
• shape based for ZipA-FtsZ protein-protein inhibition [rgm05]
  
• molecular docking based for acetylcholinesterase [mi04], PPARgamma inhibitors [lhp06]
• grid based for thrombin, protease, and neuraminidase inhibitors [blz07]
  

References

• Article (blz07)
  Bergmann, R.; Linusson, A. & Zamora, I.
  SHOP: Scaffold HOPping by GRID--Based Similarity Searches
  J Med Chem, 2007, 50, ASAP alert. DOI 10.1021/jm061259g
• Article (ga06)
  Glen, R. C. & Adams, S. E.
  Similarity Metrics and Descriptor Spaces - Which Combinations to Choose?
  QSAR & Combinatorial Science, 2006, 25, 1133 - 1142. DOI 10.1002/qsar.200610097
  
• Article (lhp06)
  Lu, I. L.; Huang, C. F.; Peng, Y. H.; Lin, Y. T.; Hsieh, H. P.; Chen, C. T.; Lien, T. W.; Lee, H. J.; Mahindroo, N.; Prakash, E.; Yueh, A.; Chen, H. Y.; Goparaju, C. M.; Chen, X.; Liao, C. C.; Chao, Y. S.; Hsu, J. T. & Wu, S. Y.
  Structure-based drug design of a novel family of PPARgamma partial agonists: virtual screening, X-ray crystallography, and in vitro/in vivo biological activities
  J Med Chem, 2006, 49, 2703-2712. DOI 10.1021/jm051129s
  
• Article (mi04)
  Mizutani, M. Y. & Itai, A.
  Efficient method for high--throughput virtual screening based on flexible docking: discovery of novel acetylcholinesterase inhibitors
  J Med Chem, 2004, 47, 4818-4828. DOI 10.1021/jm030605g
  
• Inbook (msl04)
  Maggiora, G. M.; Shanmugasundaram, V.; Lajiness, M. J.; Doman, T. N. & Schultz, M. W.
  Chemoinformatics in drug discovery A practical strategy for directed compound acquisition
  Oprea, T. I. (ed.), Wiley-VCH, 2004, 315-332.
• Article (mtg03)
  D. T. Manallack, B. G. Tehan, E. Gancia, B. D. Hudson, M. G. Ford, D. J. Livingstone, D. C. Whitley, W. R. Pitt,
  A Consensus Neural Network–Based Technique for Discriminating Soluble and Poorly Soluble Compounds,
  J. Chem. Inf. Comput. Sci., 2003, 43, 674–679. DOI 10.1021/ci0202741
• Article (nce05)
  Novellino, E.; Cosimelli, B.; Ehlardo, M.; Greco, G.; Iadanza, M.; Lavecchia, A.; Rimoli, M. G.; Sala, A.; Settimo, A. D.; Primofiore, G.; Settimo, F. D.; Taliani, S.; Motta, C. L.; Klotz, K. N.; Tuscano, D.; Trincavelli, M. L. & Martini, C.
  2-(Benzimidazol-2-yl)quinoxalines: a novel class of selective antagonists at human A(1) and A(3) adenosine receptors designed by 3D database searching
  J Med Chem, 2005, 48, 8253-8260. DOI 10.1021/jm050792d
  
• Phdthesis (ren06)
  Renner, S.
  Development and application of fast fuzzy pharmacophore-based virtual screening methods for scaffold hopping
  Johann Wolfgang Goethe–Universität, 2006. Fulltext
  
• Article (rgm05)
  Rush, T. S.; Grant, J. A.; Mosyak, L. & Nicholls, A.
  A shape--based 3-D scaffold hopping method and its application to a bacterial protein--protein interaction
  J Med Chem, 2005, 48, 1489-1495. DOI 10.1021/jm040163o
  
• Article (sam07)
  Sperandio, O.; Andrieu, O.; Miteva, M. A.; Vo, M.; Souaille, M.; Delfaud, F. & Villoutreix, B. O.
  MED--SuMoLig: A New Ligand--Based Screening Tool for Efficient Scaffold Hopping
  J Chem Inf Comput Sci, 2007, 47, ASAP alert. DOI 10.1021/ci700031v
  
• Article (ssr06)
  Schneider, G.; Schneider, P. & Renner, S.
  Scaffold-Hopping: How Far Can You Jump?
  QSAR & Combinatorial Science, 2006, 25, 1162-1171. DOI 10.1002/qsar.200610091
  
• Article (ykf06)
  Yamazaki, K.; Kusunose, N.; Fujita, K.; Sato, H.; Asano, S.; Dan, A. & Kanaoka, M.
  Identification of phosphodiesterase--1 and 5 dual inhibitors by a ligand--based virtual screening optimized for lead evolution
  Bioorg Med Chem Lett, 2006, 16, 1371-1379. DOI 10.1016/j.bmcl.2005.11.046