Quinn Ronald J, Carroll Anthony R, Pham Ngoc B, Baron Paul, Palframan Meredith E, Suraweera Lekha, Pierens Gregory K, Muresan Sorel
Eskitis Institute, Griffith University, Brisbane, Australia.
J Nat Prod. 2008 Mar;71(3):464-8. doi: 10.1021/np070526y. Epub 2008 Feb 8.
Addressing drug-like/lead-like properties of biologically active small molecules early in a lead generation program is the current paradigm within the drug discovery community. Lipinski's "rule of five" has become the most commonly used tool to assess the relationship between structures and drug-like properties. Sixty percent of the 126 140 unique compounds in The Dictionary of Natural Products had no violations of Lipinski's "rule of five". We have isolated 814 natural products based on their expected drug-like/lead-like properties to generate a natural product library (NPL) in which 85% of the isolated compounds had no Lipinski violations. The library demonstrates the feasibility of obtaining natural products known for rich chemical diversity with the required physicochemical properties for drug discovery. The knowledge generated in creation of the library of structurally characterized pure natural products may provide opportunities to front-load lead-like property space in natural product drug discovery programs.
在先导化合物发现计划的早期阶段就关注生物活性小分子的类药/类先导物性质，这是药物发现领域当前的范式。Lipinski的“五规则”已成为评估结构与类药性质之间关系最常用的工具。《天然产物词典》中126140种独特化合物中有60%未违反Lipinski的“五规则”。我们基于预期的类药/类先导物性质分离出了814种天然产物，以生成一个天然产物库（NPL），其中85%的分离化合物未违反Lipinski规则。该库证明了获得具有丰富化学多样性且具备药物发现所需物理化学性质的天然产物的可行性。在构建结构表征明确的纯天然产物库过程中所产生的知识，可能为在天然产物药物发现计划中预先填充类先导物性质空间提供机会。
