Compound library development guided by protein structure similarity clustering and natural product structure

被引:162
作者
Koch, MA
Wittenberg, LO
Basu, S
Jeyaraj, DA
Gourzoulidou, E
Reinecke, K
Odermatt, A
Waldmann, H
机构
[1] Max Planck Inst Mol Physiol, Dept Biol Chem, D-44227 Dortmund, Germany
[2] Univ Dortmund, Fachbereich Organ Chem 3, D-44227 Dortmund, Germany
[3] Univ Bern, Dept Clin Res, Div Nephrol & Hypertens, CH-3010 Bern, Switzerland
关键词
combinatorial chemistry; enzyme inhibition; bioinformatics; chemical biology; ligand-sensing core;
D O I
10.1073/pnas.0404719101
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:16721 / 16726
页数:6
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