Protein Structure Similarity Clustering

This analogy between the protein and the small molecule world led Waldmann et al. to the suggestion that there may be complementarity between the proteins and their small molecule ligands at the scaffold level, similar to the complementarity on the atomic level when interaction patterns of individual proteins and their ligands are compared 

CHAPTER 9 Biology Oriented Synthesis and Diversity Oriented Synthesis in Compound Collection Development 

FIGURE 9.13 Structural conservatism mid diversity in proteins mid their natural ligmids. 

Cdc25A 45 pM AchE 20 pM 1ipHSD1 10pM 1ipHSD2 95pM 

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Koch MA, Wittenberg LO, Basu S, Jeyaraj DA, Gourzoididou E, Reinecke K, Odermatt A, Waldmann H, Compound library development guided by protein structure similarity clustering and natural product structure, Proc Natl Acad Sci USA 101 16721-16726, 2004. 

Natural Product Scaffolds and Protein Structure Similarity Clustering (PSSC) as Inspiration Sources for Compound Library Design in Chemogenomics and Drug Development... 

PSSC as Guiding Principle for Compound Library Design 5.1. Protein structure similarity clustering (PSSC)... 

Figure 4. Nature s conservatism and diversity found in a protein structure similarity cluster. The conservatism found in the cluster can be used for the selection of pre-validated guiding structures for compound library design. The chemical diversity of the compound library is needed to address the biological diversity found in the binding sites of the cluster members.

In Chapter 3, the group of Prof. Herbert Waldmann at the Max Plank Institute for Molecular Physiology provides a rationale on how natural products which play historically a predominant role in drug discovery are efficiently used in combination with protein structure similarity clustering to inspire directed compound library design and target identification. 

M.A. Koch and H. Waldmann, Protein structure similarity clustering and natural product structure as guiding principles in drug discovery. Drug Disc. Today, 2005, 10(7), 471. 

Balamuragan, R., Dekker, F. J., Waldmann, H. Design of compound libraries based on natural product scaffolds and protein structure similarity clustering (PSSC). Mol BioSyst. 2005, 1, 36—45. 

Dekker, F.J., Koch, M.A., and Waldmann, H. (2005) Protein structure similarity clustering (PSSC) and natural product structure as inspiration sources for drug development and chemical genomics. Currr. Opin. Chem. Biol, 9, 232-239. 

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