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From Protein Domains to Drug Candidates—Natural Products as Guiding Principles in the Design and Synthesis of Compound Libraries
Author(s) -
Breinbauer Rolf,
Vetter Ingrid R.,
Waldmann Herbert
Publication year - 2002
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/1521-3773(20020816)41:16<2878::aid-anie2878>3.0.co;2-b
Subject(s) - natural product , drug discovery , function (biology) , natural (archaeology) , relevance (law) , computational biology , protein design , computer science , combinatorial chemistry , chemical biology , domain (mathematical analysis) , data science , chemistry , biology , protein structure , bioinformatics , mathematics , stereochemistry , biochemistry , evolutionary biology , paleontology , mathematical analysis , political science , law
In the continuing effort to find small molecules that alter protein function and ultimately might lead to new drugs, combinatorial chemistry has emerged as a very powerful tool. Contrary to original expectations that large libraries would result in the discovery of many hit and lead structures, it has been recognized that the biological relevance, design, and diversity of the library are more important. As the universe of conceivable compounds is almost infinite, the question arises: where is a biologically validated starting point from which to build a combinatorial library? Nature itself might provide an answer: natural products have been evolved to bind to proteins. Recent results in structural biology and bioinformatics indicate that the number of distinct protein families and folds is fairly limited. Often the same structural domain is used by many proteins in a more or less modified form created by divergent evolution. Recent progress in solid‐phase organic synthesis has enabled the synthesis of combinatorial libraries based on the structure of complex natural products. It can be envisioned that natural‐product‐based combinatorial synthesis may permit hit or lead compounds to be found with enhanced probability and quality.