title: Compound library development guided by protein structure similarity clustering and natural product structure.
abstract: To identify biologically relevant and drug-like protein ligands for medicinal chemistry and chemical biology research the grouping of proteins according to evolutionary relationships and conservation of molecular recognition is an established method. We propose to employ structure similarity clustering of the ligand-sensing cores of protein domains (PSSC) in conjunction with natural product guided compound library development as a synergistic approach for the identification of biologically prevalidated ligands with high fidelity. This is supported by the concepts that (i) in nature spatial structure is more conserved than amino acid sequence, (ii) the number of fold types characteristic for all protein domains is limited, and (iii) the underlying frameworks of natural product classes with multiple biological activities provide evolutionarily selected starting points in structural space. On the basis of domain core similarity considerations and irrespective of sequence similarity, Cdc25A phosphatase, acetylcholinesterase, and 11beta-hydroxysteroid dehydrogenases type 1 and type 2 were grouped into a similarity cluster. A 147-member compound collection derived from the naturally occurring Cdc25A inhibitor dysidiolide yielded potent and selective inhibitors of the other members of the similarity cluster with a hit rate of 2-3%. Protein structure similarity clustering may provide an experimental opportunity to identify supersites in proteins.
authors.affiliation: Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, D-44227 Dortmund, Germany.
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Koch
authors.forename: Lars-Oliver
authors.initials: LO
authors.lastname: Wittenberg
authors.forename: Sudipta
authors.initials: S
authors.lastname: Basu
authors.forename: Duraiswamy A
authors.initials: DA
authors.lastname: Jeyaraj
authors.forename: Eleni
authors.initials: E
authors.lastname: Gourzoulidou
authors.forename: Kerstin
authors.initials: K
authors.lastname: Reinecke
authors.forename: Alex
authors.initials: A
authors.lastname: Odermatt
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D000110:Acetylcholinesterase / Q000187:drug effects; D001685:Biological Factors / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D011487:Protein Conformation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors
chemical_list: D001685:Biological Factors; D004791:Enzyme Inhibitors; D042842:11-beta-Hydroxysteroid Dehydrogenases; D000110:Acetylcholinesterase; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D020687:cdc25 Phosphatases